During the last decade the development of prostate biopsy has continuously accelerated. Much has been written about the indications for biopsy, patient preparation, the potential complications associated with the procedure, and the optimum number of biopsy cores. However, minor emphasis has been placed on the problem of reducing pain during the procedure, as patient discomfort has usually been considered as a necessary part of it .
Most urologists failed to recognise a pioneering report of Nash et al. in 1996 ; these authors injected either lidocaine or saline into the nerve bundles adjacent to the prostate and patients were asked to grade the pain associated with the biopsies from each side. Patients experienced less pain on the side injected with lidocaine. After that report, negative and inconclusive results were obtained in a subsequent prospective randomized study. There was no statistically significant difference in pain between the use of anaesthetic gel and no anaesthesia, but patients who had more than six systematic biopsies taken were not considered for the evaluation .
In 2000, Soloway and Obek  stressed, for the first time, the importance of analgesia/anaesthesia as a necessary part of the biopsy procedure. They described a case series of 50 patients who received an infiltration of 5 mL of 1% lidocaine in the periprostatic neurovascular plexus, and noted that patients who had previously had biopsies indicated a noticeable difference when receiving local anaesthesia. The same group of investigators subsequently conducted a postal survey in the USA, and found that more than a third of urologists provided no analgesia in their routine practice . Since then, during the last 5 years, there has been a growing awareness of the need to adopt analgesia/anaesthesia in clinical practice when taking a TRUS-guided prostate biopsy.
For this review we systematically searched MEDLINE for clinical trials on any kind of anaesthesia, analgesia, or sedation during TRUS-guided prostate biopsy, published between 2000 and 2004. There have been an increasing number of reports in this field during this period (Fig. 1).
We discuss the following points: the impact of pain and discomfort associated with the procedure, the different techniques that have been described, the evaluation of the results and the comparisons made, and which definitive conclusions can be drawn.
PAIN DURING PROSTATE BIOPSY: DOES THE PROBLEM EXIST?
Men having a transrectal prostate biopsy taken, experience considerable psychological stress that may be attributable to the fear of the potential diagnosis of cancer, the anal route of penetration, that the examined organ is part of the male sexual system, and the anticipated pain. Therefore, although most of the morbidity associated with the procedure involves minor complications, patients perceive it as traumatic and worrisome.
It is every urologist's experience that anxiety is common in men attending for a biopsy, and that those men who are most anxious are most likely to experience pain. Problems have also arisen in men requiring a second TRUS-guided biopsy, as they often have unpleasant memories from the first procedure. Occasionally the patient can become diaphoretic because of the degree of discomfort, and this is not helpful to the clinician, who should have the opportunity to take time to accurately locate suspicious areas and target the biopsy needle at specific sites.
A study published in 1999 by Crundwell et al. examined the patient's perspective during the prostatic biopsy. Given that no analgesia or sedation was used in their centre, they reported moderate to severe pain in almost a quarter of their patients, a proportion similar to those reported in two previous studies [7,8]. Irani et al. found that 19% of 81 patients would refuse to undergo further TRUS and biopsy with no analgesia. Collins et al. reported that 22% of 89 men undergoing TRUS biopsy with a minimum of six cores had found the procedure painful.
In contrast, Aus et al. recorded moderate to severe pain in only 7% of 343 patients undergoing biopsy, but the mean number of cores was only 2.6, which may account for the difference. Similarly, Bastide et al. found that 80% of the patients reported acceptable discomfort, with almost half of their study population having six or fewer cores taken. The same authors suggested that it is important to identify risk factors associated with a painful biopsy, to select the patients who may benefit from anaesthesia. According to their report some indications already seemed clear; patients (possibly mostly younger men), who are anxious, in whom more extensive biopsy is planned, or who would require a repeat biopsy.
The optimum number of biopsy cores for detecting prostate cancer is a matter of debate and most studies indicate that extensive biopsy protocols may improve cancer detection . In this setting there is concern about patient tolerance of such protocols. The discomfort during transrectal biopsy appears to be proportional to the number of cores taken, even if some authors do not agree on this point. Chang et al. noted no correlation between the number of biopsies taken and the pain score, but they determined that age independently had a significant effect on pain perception. Younger patients had significantly more pain than older ones. Analysing pain and morbidity associated with an extensive TRUS-guided 10-core biopsy protocol, Peyromaure et al. found that only 47.6% of 275 patients described the procedure as painful, and mild in two-thirds, on a visual analogue scale, when given adequate information before the procedure. By prospectively comparing a 12- with a 6-core biopsy protocol Naughton et al. reported no statistically significant difference in the two procedures for any mean pain level at biopsy or subsequently.
Zisman et al. evaluated the impact of prostate biopsy on patient well-being in 211 consecutive men in whom a mean of eight biopsy cores was obtained. Immediate pain or discomfort was experienced during the procedure by 96% and 89% of their patients, respectively. The authors noted how their results were very different from those obtained in the study by Clements et al., who found only 7% of patients considered the procedure to be painful, with 32% of them feeling no pain or discomfort during biopsy. The difference has been attributed to variation in the definitions of pain and discomfort, and to different biopsy strategies, as Clements et al. sampled no more than five cores in a lesion-orientated fashion, whereas Zisman et al. obtained a median of eight cores randomly.
Another issue is the concept of ‘pain accumulation’ that has been introduced by Kaver et al.. They found that the pain during biopsy gradually accumulated from the first core to the last, even when anaesthesia is administered. Their study remains the only report to address the pain score at the time of biopsy after each sample.
WHICH TECHNIQUES HAVE BEEN DESCRIBED?
To reduce the pain associated with TRUS-guided prostate biopsy different methods have been introduced (Table 1) [2–4,11,16–28], e.g. local anaesthesia (periprostatic nerve block), intrarectal anaesthetic gel, sedation, and analgesia.
Table 1. Reducing pain during prostate biopsy: which technique?
The two factors usually responsible for pain during prostate biopsy are anal discomfort from the ultrasound probe and insertion of needles through the prostate gland. As the biopsy needle pierces the rectal wall in an area of decreased sensorium above the dentate line, most pain associated with prostate biopsy is caused by the needle penetrating the prostatic capsule. This penetration results in periprostatic nerve stimulation of sensory receptors located in the capsule. Because of the anaesthetic blockage of capsular sensitive fibres, the patient feels less anxious and more relaxed, not contracting the pelvic muscles, making the examination more tolerable. Furthermore, there is some degree of systemic drug absorption resulting from the great absorptive capacity of rectal mucosa.
Different amounts of anaesthetic medium and different injection sites have been proposed for local anaesthesia during TRUS-guided prostate biopsy. Nash et al. initially suggested bilateral injections at the junction of the base of the prostate and seminal vesicles. Soloway and Obek  proposed a modified version of the periprostatic nerve block, recommending two more injections on each side, one beside the apex and one between the apex and the base. Combining both techniques, Kaver et al. found that lateral and apical periprostatic anaesthesia significantly diminished the pain in men undergoing prostate biopsy. Conversely, Wu et al. found no benefit in 5 mL of lidocaine infiltration injected laterally to the seminal vesicles bilaterally, compared with the placebo, but this result could be explained by the few patients (only 40 randomized). It is also possible that the local dose of lidocaine deposited on each side of the seminal vesicles was insufficient to produce analgesia.
Seymour et al. empirically developed another method of periprostatic infiltration only at the apex. They considered that the neurovascular bundles pass along the posterolateral margins of the gland between the capsule and Denonvilliers’ fascia, and pierce the capsule particularly at the base and apex in the 4 and 8 o’clock positions. Thus, anaesthetic introduced at these points will numb the entire gland. Interestingly, they found no apparent difference in pain between those patients having multiple and sextant biopsy. The efficacy of their method was confirmed by Rodriguez et al., who found that infiltrating lidocaine at each side of the apex is sufficient to control pain, because the lidocaine bolus of 10 mL extends under Denonvilliers’ fascia up to the lateral borders of the prostate and seminal vesicle-prostatic angles. Schostak et al. compared four groups of patients undergoing no local anaesthesia, anaesthetic block of the prostatic plexus, local anaesthesia onto the capsule of the apex and a combination of the two previous methods. They found that all types of local anaesthesia lead to lower pain scores. The most effective was apical infiltration, which was easy and technically less difficult than anaesthetic block, with minimal invasiveness and morbidity.
Also Taverna et al. adopted a single bolus of 10 mL lidocaine but administered at the prostatic midline between Denonvilliers’ fascia and the periprostatic fascia overlying the prostate. They found this option to be safe, well tolerated and effective without increasing adverse effects.
Matlaga et al. described a novel and effective means of local anaesthesia. According to their technique, the lidocaine is injected as follows: 5 mL into both the left and the right nerve plexus located at the junction of the seminal vesicle and prostate, 5 mL into the genitourinary diaphragm and 5–7 mL between the rectal wall and the prostate.
Berger et al. suggested using less (2 mL each side) of a more concentrated lidocaine (2% instead of 1%). Von Knobloch et al. studied the efficacy of 1% articaine, a fast-acting anaesthetic similar to lidocaine, injected posterolaterally in the region of neurovascular bundles bilaterally. Ozden et al. conducted a randomized study to evaluate the efficiency of various amounts of local anaesthesia at different locations and numbers to identify the most effective pain control with the fewest injections and amount of injected medium. They used TRUS-guided eight-core biopsy in 175 patients, randomized into seven different groups: group 1 receiving saline and groups 2–7 received 2.5, 5 and 10 mL of 1% lidocaine injected at basal or at basal plus apical locations. Their results showed that 10 mL of local anaesthetic gave significantly better pain control than lower doses. Basal plus apical injections were no better than basal multiple injections only for the pain control. Inal et al. found that 6 mL of 1% lidocaine is sufficient to obtain a safe and easy anaesthesia
Lee-Elliott et al. were the first to advocate the combination of the long-acting local anaesthetic bupivacaine to lidocaine to significantly attenuate the ‘rebound’ increase in pain scores apparent after the short-acting anaesthesia alone. Subsequently, Rabets et al. found bupivacaine to be as effective as the lidocaine/bupivacaine combination in providing significant immediate anaesthesia. They injected anaesthetics into the hyperechoic notch between the prostate and the seminal vesicle, which they termed ‘the Mount Everest sign’.
Anaesthetic gel instillation
It was proposed that intrarectal lidocaine gel could be a suitable form of anaesthesia before prostate biopsy, because it is easy to administer. Issa et al. recommended the routine administration of 2% lidocaine gel, because of a significant difference in the median pain score compared with the placebo jelly. Their findings were questioned more recently by Chang et al., who randomized 108 men in a double-blind trial; they explained this difference with the different type of pain scale used, that their study was double-blind and that Issa et al. excluded patients with a history of biopsy.
While general anaesthesia may overcome the pain during TRUS-guided prostate biopsy, it is not without risk. There remains a demand for an agent that would improve patient tolerance of this procedure while allowing it to be performed on an outpatient basis. Ideally it should have a rapid onset of effect, be easily reversible and have minimal side-effects. Entonox is a gaseous anaesthetic agent (50% nitrous oxide and 50% oxygen) that is widely used in the UK to provide analgesia during labour, and for minor procedures in the accident and emergency department. It provides analgesia within 3 min of inhalation and this analgesic effect disappears in < 4 min after cessation. In a short-term, placebo controlled double-blind trial, Masood et al. described significant analgesic benefits with Entonox inhalation for the procedural related pain or discomfort of prostate biopsy.
The study of Peters et al. remains the only one to address the use of propofol for sedation during prostate biopsy. They found significantly reduced discomfort, especially for patients who need repeated prostatic biopsies. The authors also emphasized the need for a cost analysis; obviously, propofol anaesthesia needed operating theatre conditions, increasing the cost.
There are two published randomized placebo-controlled trials on the use of NSAIDS. Moinzadeh et al. studied the potential use of rofecoxib, a selective cyclooxygenase-2 inhibitor, given orally 1–2 h before biopsy, as a form of pre-biopsy medication. They found the same overall mean pain level between the placebo and rofecoxib groups, and concluded that there is no role for this drug in this setting. However, Haq et al. found that diclofenac suppositories 1 h before biopsy decreased patient discomfort associated with the procedure, improving patient tolerance with no significant increase in morbidity.
HOW TO EVALUATE THE OUTCOME?
Pain and discomfort
Pain is a complex perceptual experience that is difficult to quantify. Interpreting the results in terms of pain and discomfort during TRUS-guided biopsy remains subjective and there are no standardized criteria to define whether a given procedure is well tolerated or not. Different methods have been used for this purpose and this bias must be considered when analysing the outcome from the different experiences.
In the report of Desgrandchamps et al., at the end of the procedure patients were asked to score the severity of discomfort using a self-administered verbal rating scale, which consisted of a list of adjectives describing different levels of pain, from none to intolerable pain. In the last three decades the visual analogue scale (VAS) has proven to be satisfactory for subjectively measuring pain intensity. It is independent of language, after instruction, provides a sensitive measure and enables statistical comparison. In several studies the patients were asked to grade the discomfort and/or pain level experienced during the procedure using a 11-point (from 0 to 10) linear VAS, that is easily comprehensible to patients, particularly the elderly, and easy to administer. VAS scores from 4 to 7 typically correspond to a rating of moderate pain on four-point categorical pain intensity scale (none, mild, moderate and severe). A modification to this rating was proposed by some authors, e.g. Masood et al., who considered 0 as no pain, 1–3 as slight, 4–6 as moderate, 7–9 as severe, and 10 as unbearable pain . Similarly, Kaver et al. used a five-point scale, with 0, 2.5, 5, 7.5 and 10 as thresholds.
In their study, Chang et al. used a linear scale with no numbers instead of a 10-point linear VAS, to avoid limiting the discriminatory ability of a numbered scale. Similarly, Wu et al. used an unmarked 10-cm line, with ‘no pain’ at left and ‘worst pain imaginable’ at the right end of the line. In the report by Rodriguez et al. patients were asked to grade the discomfort/pain level experienced using a 10-point linear VAS and a 5-point digital visual pain scale (1, no pain; 2, mild; 3, moderate; 4, severe; 5, unendurable pain).
In some cases, besides the VAS, patients were given a specific questionnaire to be completed [17,25], e.g. Stirling et al. used four different questions to analyse the overall impression of the procedure, the probe insertion, the biopsy portion and the willingness to return for the procedure, respectively.
Before any procedure can be accepted as a standard, any associated morbidity must be explored. Periprostatic local anaesthesia requires one or more extra needle punctures and it can be expected that these extra punctures may increase complications.
Obek et al. specifically designed a study to assess morbidity associated with the method. No dizziness, visual disturbance, tinnitus, and respiratory distress, potential side-effects associated with the absorption of lidocaine were reported. The authors emphasized the importance of syringe aspiration before injection, to avoid inadvertent entry into the vascular system. Moreover, they reported that periprostatic local anaesthesia did not increase the risk of urethral bleeding. They considered that an increase in haematuria is unexpected because the anaesthetic is infiltrated in a region far from the urethra.
Ozden et al. were the first to compare complication rates according to the number of injections, in the same series. They showed that giving more injections had no effect on haematuria rates. The results were similar for haematospermia and rectal bleeding. Obek et al. reported a lower incidence of rectal bleeding with local anaesthetic use and concluded that it may be related to decreased patient discomfort.
Another aspect to be considered is whether periprostatic local anaesthesia is associated with a higher incidence of infectious complications. Because the rectum is highly colonized by bacteria, each extra needle puncture may increase the risk of infection . In the study by Taverna et al. there were no patients with high fever in those injected with local anaesthetic. Seymour et al. also found no difference in fever between groups injected with local anaesthetic or not. Results from Ozden et al. showed that the number of injections did not change the incidence of fever significantly, nor did the amount of anaesthesia injected. Obek et al. suggested a prospective randomized trial to establish the optimum antibiotic prophylaxis in men undergoing prostate biopsy with nerve block.
The theoretical concern of increased scarring from injection in the neurovascular bundles has not been reported to make nerve-sparing prostatectomies more difficult. Moreover, there was no significant difference in postoperative continence or impotency rates .
Alavi et al. reported the first randomized study comparing the efficacy of periprostatic infiltration under TRUS guidance with intrarectal instillation of anaesthetic gel before TRUS. Since their report, another seven comparative randomized trials have been conducted (Table 2) [20,22,29,34,37–40].
Table 2. Results from prospective randomized studies comparing gel instillation and drug infiltration
Mean N cores
Mean VAS score, (0–10 scale)
overall evaluation at the end of the procedure;
partial evaluation during anaesthesia, during biopsy procedure and after 30 min, respectively.
0.1 vs 1.4 (P < 0.001)† 2 vs 2.6 (P = 0.15) 0.8 vs 1.4 (P < 0.001)
Because it is simple to administer lidocaine gel should be used before prostate biopsy
Stirling et al. found that both forms of local anaesthesia are effective in reducing patient discomfort during the procedure. Patients who received intrarectal lidocaine had significantly lower mean pain scores for probe insertion, while those receiving periprostatic injections had mean pain scores significantly lower for the biopsy portion of the procedure. In another study by Lynn et al. periprostatic nerve block gave better analgesia than rectal lidocaine instillation or placebo. Although rectal lidocaine reduced the pain score, the difference was not statistically significant from the placebo. These findings were corroborated by those of Adamakis et al., who confirmed the superiority of periprostatic injection of lidocaine over anaesthetic cream instillation. In their prospective randomized study, Rodriguez et al. concluded that lidocaine infiltration at the apex is sufficient for pain control, does not increase the rates of complications, nor the difficulty of dissecting the apex during radical prostatectomy.
The only study not confirming the superiority of lidocaine infiltration vs lidocaine gel was that by Mallick et al., who found that patients having intrarectal administration of lidocaine gel had lower mean pain scores than those treated with periprostatic lidocaine infiltration, with significant VAS score differences during anaesthesia and 30 min after the biopsy. Therefore, they did not recommend anaesthesia by lidocaine infiltration.
Importantly, in the study by Alavi et al. and in the others noted, the number of cores obtained per patient was 6–10, and none of the investigators used an extensive prostate biopsy protocol. In the study by Matlaga et al. all the patients tolerated the saturation biopsy procedure well, with minimal discomfort. The authors explained that lidocaine jelly provided ineffective anaesthesia, probably because a sufficient concentration of drug was never delivered to the prostatic nerves.
To compare the efficacy of Entonox with periprostatic lidocaine infiltration, Manikandan et al. included 235 patients in a prospective randomized trial, finding that both techniques are safe, effective and inexpensive. However, they recommended considering a few cautions and contraindications before administering Entonox. It should not be used in patients with congestive cardiac failure and significant chronic obstructive airway disease.
Obek et al. randomized 300 patients into four groups: controls, periprostatic nerve block, lidocaine gel plus prostatic nerve block and tramadol, a centrally acting synthetic analogue of codeine. They concluded that any form of analgesia/anaesthesia used was better than none. The combination of periprostatic nerve block and lidocaine gel provided significantly better analgesia. They suggested lidocaine gel can obviate two shortcomings of periprostatic nerve block alone: needle insertion for anaesthetic infiltration, that can be painful for the patient, and ultrasound probe insertion, that for some men is just unacceptable. Tramadol was the only totally complication-free method and could be a viable alternative that needs to be explored.
A substantial number of patients experience moderate to severe pain during TRUS-guided prostate biopsy. There is now sufficient published evidence that anaesthesia/analgesia improve patient tolerance and comfort, and we would urge all urologists to introduce it in their clinical practice as a routine part of the procedure, whatever the patient and biopsy scheme. Among the various options, periprostatic anaesthetic infiltration (alone or associated with lidocaine gel) is safe, easy to perform, highly effective and can be considered the ‘gold standard’ at the moment, even if the optimum technique remains to be established.