Introduction

Trans-rectal ultrasound (TRUS) with prostate biopsy is used with increasing frequency to diagnose prostate cancer. Many men require repeated biopsy and the number of samples obtained is increasing to improve diagnostic accuracy. Since up to a quarter of patients find the procedure moderately to extremely painful,¹ there is considerable interest in identifying effective analgesia that would nonetheless preserve the outpatient nature of this procedure. Most studies so far have used lignocaine delivered by either periprostatic injection or by rectal instillation of gel. While lignocaine injection seems to be an effective analgesic^2,3,4 the usefulness of intrarectal lignocaine gel is uncertain.^5,6,7

Entonox is a gaseous anaesthetic agent with strong analgesic properties commonly used in Accident and Emergency and Obstetric departments. It is easy to administer, acts systemically with rapid onset and has a short duration of action with few side effects. Entonox is not widely used as an analgesic for outpatient procedures, although it has recently been shown to provide effective analgesia for colonoscopy.⁸ To date, one other study has investigated its use in conjunction with prostate biopsy.⁹

We carried out a double-blind, randomised controlled study to establish whether the use of Entonox provides suitable analgesia during prostate biopsy.

Patients and methods

Patients

Local research ethics committee approval for the study was obtained. A total of 50 consecutive patients attending for TRUS-guided prostate biopsy to investigate raised serum prostate-specific antibody (PSA) or an abnormal feeling prostate were sent written information about the study in advance of their biopsy appointment. This included advice that they would not be able to drive for 12 h if they chose to participate. Those who had previous TRUS, pelvic irradiation, prostatitis, painful anal conditions, who were on anticoagulants, or who had significant respiratory or cognitive impairment were excluded, as were patients who wished to drive home after their biopsy.

Entonox administration

Patients were randomised to breathe either Entonox or room air for 5 min prior to and during their TRUS-guided biopsy. After randomisation, they inhaled the appropriate gas through a mouthpiece with a Y-connection attaching two 2-m long plastic tubes one of which was open to air and the other connected to an Entonox cylinder (Entonox—50% nitrous oxide and 50% oxygen). If the patient was randomised to breathe air, the air tube was left open and the Entonox regulator turned off. Conversely, if he was randomised to breathe Entonox, the Entonox regulator was turned on and the air tube was plugged off.

TRUS technique

With the patient breathing the appropriate gas in the left lateral position, TRUS was performed with a 7.5 MHz biplanar probe (Kretz Technic, Combison 330). The maximum anteroposterior and transverse diameters of the prostate were recorded and sextant biopsies were taken using an 18G biopsy needle by the same surgeon who used exactly the same biopsy technique for all 50 patients. All patients received a quinolone antibiotic before and for 3 days after the procedure. Randomisation, administration of Entonox or air and collection of pain information were carried out by the same nurse in all cases. No other assistance was required during the procedure. Neither the patient nor the surgeon was aware of which gas was used.

Recording of pain scores

10 min after the procedure, the patient was asked to record the amount of discomfort experienced on a 100 mm long visual analogue scale (VAS) and whether he would undergo a repeat biopsy under the same conditions. The surgeon recorded whether he felt that the patient had experienced significant discomfort or not. The patients' serum PSA, prostatic volume, DRE findings and eventual histology were also recorded. Prostatic volume was calculated using the following formula:¹⁰

A preliminary sample size calculation based on data collected in a pilot study showed that 25 patients would be needed in each group to have 85% power to detect a clinically relevant between-group difference in VAS of 20 mm.

Results

Patient characteristics

In all, 50 patients were enrolled into the study and randomised to give 25 in the air-breathing group and 25 in the Entonox group. A further 17 patients were invited to take part in the study but wished to drive themselves home and were excluded. The two groups were comparable in age and histological outcome (Table 1). However, the median prostate volume was slightly higher and the median PSA slightly lower in the Entonox group than in the air group.

Table 1 - Patient age, prostate volume, serum PSA and biopsy histology for the air- and Entonox-breathing groups.

Full table

Median pain scores

The median pain score of the Entonox group was 11 mm and that of the air group was significantly higher at 34 mm (P<0.001—Mann–Whitney U-test). Although there was some degree of imbalance between the groups in terms of median PSA and prostate volume, neither of these was prognostic for their VAS pain score (Figure 1).

Figure 1.

(a) Relationship between visual analogue pain score (VAS) and prostate volume, by treatment group. (b) Relationship between VAS pain score and log PSA, by treatment group.

Full figure and legend (26K)

Pain score distributions

The distributions of VAS results are shown graphically in Figure 2. In the Entonox-treated group 21/25 (84%) had VAS scores between 0 and 24, whereas in those breathing air 15/25 (60%) had scores between 25 and 49. Two patients in the air group (VAS scores 31 and 45) and one in the Entonox group (VAS score 92) said that they would refuse another biopsy under similar conditions. Two patients in the Entonox and one in the air group had high pain scores. The first on Entonox recorded a pain score of 80 but seemed comfortable during the procedure and stated he would be happy to have the biopsy repeated under the same conditions. The second recorded a pain score of 92, seemed very uncomfortable and said that he would refuse further biopsy. He also stated during the procedure that he thought that he was breathing air. This was despite the fact that patients were not asked any questions during TRUS in case their answers interfered with them breathing the gas. One patient breathing air recorded a pain score of 63. He seemed very uncomfortable during the procedure yet said that he would be prepared to go through with it again.

Figure 2.

Bar chart showing visual analogue pain scores (VAS) for patients breathing Entonox and air.

Full figure and legend (58K)

There was only one hospital admission which was a patient from the Entonox group who developed moderate sepsis which responded rapidly to parenteral antibiotics.

Discussion

The number of patients requiring prostate biopsy in our institution is continually rising and it is clear that without analgesia many experience significant pain. Our median pain score of 34 in the placebo group is similar to that reported by others.^2,7 Such pain may be worsened by increased sampling, patient anxiety, the prospect of repeated biopsy and previous radiotherapy. Furthermore, in our experience, the apical biopsies seem the most painful, possibly relating to probe angulation or needle entry close to the anal canal. We controlled for these factors in this study by excluding all those patients who had had any previous treatment to their prostate or previous prostate biopsy and by having the same surgeon do all the biopsies using exactly the same technique.

Pain associated with prostatic biopsy is caused by the needle penetration of prostatic capsule. Hollabaugh et al¹¹ outlined the nerve supply to the prostate from the inferior hypogastric plexus located at the apex of the seminal vesicles and passing posteriolaterally along the neurovascular bundles to the prostate. Intrarectal lignocaine gel is thought to reach these nerves by diffusion through the rectal wall. Lignocaine gel analgesia is, however, of unproven value due to conflicting results from different investigators.^6,7 The majority of studies investigating the effect of lignocaine injection have shown that it provides effective analgesia.^2,3,4 However, one recent randomised study failed to demonstrate any benefit from lignocaine injection.¹² Moreover, it may be difficult to identify the location of the prostatic nerve supply during TRUS thus causing inaccuracy with the delivery of the lignocaine injection. Intravenous sedation or even general anaesthesia is often used on the rare occasions when patients have to undergo very large numbers of prostate biopsies.¹³

Entonox requires no skill to administer, nor does it require the presence of any additional nursing or medical staff. It has a very rapid onset of action and, although we asked patients to breathe it for 5 min before TRUS in this study, this length of prebreathing may be unnecessary. The results of the study suggest that Entonox reduces the amount of pain experienced by patients during standard sextant prostate biopsy. Our findings support those of a recent study by Masood et al,⁹ who also found a significant difference in the mean pain score experienced by patients breathing air and Entonox. Entonox could be used in combination with local anaesthesia for particularly anxious patients.

None of the patients breathing Entonox in our study suffered any side effects, respiratory problems or prolonged drowsiness. We therefore feel that it is quite safe and appropriate to use Entonox in the outpatient setting. Moreover, recent evidence has shown that Entonox has a rapid offset of action and does not affect the performance of complex motor skills tested shortly after inhalation.¹⁴ However, at the present time, the manufacturers of Entonox, BOC gases, recommend that patients should not drive within 12 h of breathing the gas. We would therefore suggest that patients are informed about Entonox analgesia before their biopsy appointment so that they have the opportunity to make alternative transport arrangements. It could also be argued that patients undergoing TRUS with its risks of sepsis and haemorrhage should not be driving immediately afterwards anyway.

In conclusion, this study shows that Entonox is an effective method of analgesia for prostate biopsy in the vast majority of cases. It is safe and easy to administer. We now offer Entonox routinely to patients attending for TRUS at our institution.

References

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Acknowledgements

We wish to thank Dr Chris Sutton for statistical advice and Miss Ling Lee and Miss Gillian Mobb for allowing us to recruit their patients into this study.