DICLOFENAC SUPPOSITORY ANALGESIA FOR TRANSRECTAL ULTRASOUND GUIDED BIOPSIES OF THE PROSTATE: A DOUBLE-BLIND, RANDOMIZED CONTROLLED TRIAL

0022-5347/04/1714-1489/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 171, 1489 –1491, April 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000115706.19605.e4

DICLOFENAC SUPPOSITORY ANALGESIA FOR TRANSRECTAL ULTRASOUND GUIDED BIOPSIES OF THE PROSTATE: A DOUBLEBLIND, RANDOMIZED CONTROLLED TRIAL A. HAQ, H. R. H. PATEL,* M. R. HABIB, P. J. DONALDSON

AND

J. R. W. PARRY

From the Department of Urology, Ipswich Hospital, Ipswich and Institute of Urology and Nephrology, University College London (HRHP), London, United Kingdom

ABSTRACT

Purpose: A significant proportion of men undergoing transrectal ultrasound (TRUS) and prostate biopsy report pain during the procedure. A number of different methods of pain relief have been suggested in the literature. We prospectively evaluated the effect of diclofenac suppositories on pain experienced by men undergoing TRUS and prostate biopsy. Materials and Methods: A prospective, randomized, double-blind, placebo controlled study was performed in 72 patients requiring prostate biopsy. Patients were randomly assigned to receive 100 mg diclofenac or placebo 1 hour prior to the procedure. They were asked to indicate on a 10 cm visual analogue scale the degree of discomfort during the procedure. The patients were then seen 2 weeks later and any morbidity, including infection and bleeding, was assessed. Results: Patients given diclofenac had significantly lower pain scores than those given placebo (2.8 vs 4.9, p ⬍0.001). The 2 groups were similar in regard to age, prostate volume, biopsy number, prostate specific antigen, histological diagnosis and complication rate. Conclusions: Rectal administration of diclofenac 1 hour prior to TRUS and prostate biopsy is a simple procedure that significantly relieves the pain experienced with no increase in morbidity. With the trend toward more core samples, screening for prostate cancer and the younger age of patients undergoing biopsy we urge urologists to provide analgesia for this painful procedure. KEY WORDS: prostate, biopsy, pain, diclofenac, suppositories

Clinical experience suggests that a significant proportion of patients considers transrectal ultrasound guided biopsy of the prostate (TRUSP) uncomfortable or sometimes painful. Crundwell et al found that 24% of patients undergoing TRUSP and biopsy thought that the procedure was moderate to severely painful with pain scores greater than 5 on an analogue scale of 0 to 10.1 Moreover, Irani et al found that 19% of men would not undergo the procedure again without some form of analgesia or anesthesia.2 Methods of analgesia that have been suggested in the recent literature include the rectal administration of lidocaine gel and lidocaine suppositories,3 which showed no significant benefit with regard to pain relief. In addition, sedoanalgesia4 and inhalational agents5 have also been suggested. Transrectal ultrasound guided nerve blockade using lignocaine infiltration into the prostatic vascular pedicle has been suggested as an alternative method of pain relief,6 although operator variability and the increased infection risk are significant concerns. Diclofenac suppositories are easily administered and safe in the majority of patients. To our knowledge there have been no previous studies of rectal diclofenac prior to TRUSP and biopsy. We recently performed an open, unblinded, proof of principle study of the role of diclofenac for analgesia prior to TRUSP and biopsy because it is a more practical alternative to transrectal infiltration of local anesthesia. Our pilot study showed not only that TRUSP and biopsy are often a painful experience, but also there was a statistically significant improvement in pain scores in patients administered vs not

administered rectal diclofenac 1 hour prior to the procedure and no increase in complication rates.7 Since to our knowledge no placebo controlled studies have assessed the role of diclofenac prior to TRUSP and prostate biopsy, we performed a prospective, randomized double-blind, placebo controlled trial. PATIENTS AND METHODS

This study conforms to standards for Reporting Diagnostic Accuracy guidelines for testing accuracy.8 Standard practice at our unit at that time was to give no analgesia. Hence, a placebo group was deemed to be ethical. Fully informed patients who provided consent were invited to participate at our urological clinic at Ipswich Hospital. Patients were prospectively entered into the study following a certain protocol. Patients and randomization. All patients referred to the TRUSP and biopsy clinic in an 8-month period were eligible for the study. All patients had a recognized indication for biopsy (age matched, elevated prostate specific antigen [PSA] or abnormal digital rectal examination). The only exclusion criterion was a known contraindication to nonsteroidal antiinflammatory medication. Patients were informed that they were participating in a double-blind, placebo controlled study and the chance of being randomized to the diclofenac or placebo group was 50%. The 72 patients who agreed to the study were randomized by code labeling and random code number generation by computer software. Suppositories were identically packaged and numbered with the patient and operator blinded to the exact nature of the suppository. Biopsy protocol. Patients randomized to the analgesia group received a diclofenac suppository (100 mg) 1 hour prior to the procedure at the same time as antibiotic prophylaxis (500 mg ciprofloxacin). Patients randomized to the placebo

Accepted for publication November 7, 2003. Study received local ethics committee approval. * Correspondence: Institute of Urology and Nephrology, University College London, 48, Riding House St., London, W1W 7EY, United Kingdom (telephone: 02076799381; e-mail: hitendra.patel@ ucl.ac.uk). 1489

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DICLOFENAC FOR PROSTATE BIOPSY

group received an identical placebo suppository 1 hour prior to TRUSP and biopsy. Patients were placed in the lateral decubitus position. TRUSP biopsy was performed by one of us (MRH or PJD) using a 6.5 MHz transrectal probe. An average of 8 prostate biopsies were taken using a Magnum Biopsy Gun (C. R. Bard, Murray Hill, New Jersey), a spring loaded biopsy gun needle with an 18 gauge, 20 cm needle. Outcomes measures. Directly after the procedure patients were asked to show on a 10 cm linear visual analogue scale the degree of discomfort experienced during the procedure. A questionnaire of patient details and the number of biopsies performed in addition to the identification number of the suppository administered was completed. Two weeks after biopsy patients were informed about the histological results and about complications such as infection, bleeding and gastrointestinal upset, which were recorded. Statistics. The sample size calculation with 2 groups in the study was based on a difference in pain scores of 1, SD of 1, type 1 error (␣) of 0.01 and a power of 95% (1-␤). The sample size necessary to show a significant difference was estimated to be 35 patients per arm. The difference between the 2 groups in volume, age and pain scores was tested with the independent samples t test. PSA and the number of biopsies were tested using the Mann-Whitney U test. The percent of patients with complications were tested using the chi-square test. RESULTS

Of the 72 patients included in the study 37 were in the treatment arm and 35 received placebo. There was no significant difference in mean age in the treatment and controls groups (67.9 vs 65.1 years, p ⫽ 0.07). Mean prostatic volume in the treatment and control arms was 50.4 and 48 ml, respectively (p ⫽ 0.3). An average of 8 biopsies was taken per patient (range 4 to 12 per group) and the median number of biopsies per group was 8. There was no statistical difference in PSA in each group. A significant difference in mean pain score in the treatment vs the control group was noted (2.8 vs 4.9, p ⬍0.001, table 1). In the treatment arm 4 patients had pain scores greater than 5 compared with 11 in the placebo group. In the treatment group 32% of patients complained of hematuria with 1 requiring general anesthesia cystoscopy and clot evacuation for significant hemorrhage not responding to conservative measures. In the control group 37% of patients complained of hematuria after the procedure and 1 had a symptomatic urinary tract infection. In the treatment group 43% of patients had a diagnosis of carcinoma and in the control group carcinoma was diagnosed in 48% (table 2). DISCUSSION

Pain associated with prostate biopsy is attributable to insertion of the ultrasound probe and needle puncture into the TABLE 1. Findings in the control vs the treatment group Group

No. Pts

Mean*

95% CI

Pain score: Treatment 37 2.8 0.7 Placebo 35 4.9 0.9 Age: Treatment 37 67.9 0.6 Placebo 35 65.1 2.5 Vol: Treatment 37 50.4 6.8 Placebo 35 48 6 PSA (ng/ml): Treatment 37 18 8.3 Placebo 35 16 6.7 No. biopsies: Treatment 37 8.1 0.6 Placebo 35 8.6 0.6 * Treatment and placebo SD 2.28 and 2.29, respectively.

p Value 0.001 0.07 0.3 0.36 0.10

TABLE 2. Histology and clinical complications Group Complications: Treatment Placebo Benign histology: Treatment Placebo

No. Pts (%)

Chi-Square

p Value

37 (32.4) 35 (40)

0.446

0.50

37 (56.8) 35 (51.4)

0.206

0.65

prostate. Prostatic pain predominantly arises in the prostate capsule or stroma, which has a rich innervation of autonomic fibers but more importantly C-fibers. These fibers convey sensation to the spinal cord. Parasympathetic innervation of the prostate is derived from the caudal roots of S2 to S5 and the sympathetic chain via the presacral and hypogastric neural plexuses. These fibers ramify in the prostatic plexus and travel in the prostatic vascular pedicles. Our assessment of intraprocedure pain was in actuality determined immediately after biopsy, not during biopsy. We suggest that recall bias was minimal due to the short interval between the actual biopsy and pain assessment (less than 5 minutes). Because of personal and positional considerations, we did not believe that it was appropriate to ask our patients to mark the pain level during the actual biopsy procedure. A number of studies have shown that younger patients have more discomfort during biopsy than their older counterparts.9, 10 In addition, patients with a smaller prostate have increased pain, as do those with inflammatory changes within the prostate gland. Pain following the procedure may be associated with the production of potent local mediators, such as cytokines, prostaglandins and leukotrienes, leading to local pain, edema and the recruitment of other immune competent cells.11 Diclofenac acts locally and systemically as an anti-inflammatory and it decreases the effects of local mediators involved in the pain response. Diclofenac may be given orally but we believe that its beneficial local effect would then be lost. Our study clearly showed improved comfort in patients after diclofenac treatment. This group showed no obvious differences compared to controls or to the published literature in terms of complications. A patient in the diclofenac group had significant hematuria following biopsy, which did not settle with conservative management and required formal bladder washout using general anesthesia. Diclofenac had no effect on hematological parameters, specifically clotting indexes were normal. A patient in the study had a symptomatic urinary tract infection (control group) despite antibiotic prophylaxis. Other suggested methods of analgesia include lidocaine gel and suppositories, which have not shown a significant benefit for pain relief. The injection of periprostatic local anesthesia has been shown to produce a benefit in pain relief in prospective studies. However, the prospective, double-blind, placebo controlled trial of Wu et al of periprostatic lidocaine vs sterile normal saline revealed no significant differences in pain scores between the control and treatment groups.12 Concerns about the potential of increased infection have been suggested regarding periprostatic local anesthetic infiltration. The administration of periprostatic local anesthesia may result in fibrosis and interfere with nerve sparing radical prostatectomy.13 Local anesthesia alone may cause a mild stinging sensation when injected into prostatic vascular pedicle and incorrect injection in the midline (into the external sphincter or urethra) is painful.14 In addition, we suggest that there is a degree of user variability in the injection of local anesthesia into the correct anatomical position, which to our knowledge has not been addressed in the literature. Patients who undergo transurethral prostate resection may have distorted anatomy, which could decrease the effectiveness of local anesthetic administration. Seminal vesicle biopsies remain painful despite adequate prostatic anesthesia.14

DICLOFENAC FOR PROSTATE BIOPSY

The administration of diclofenac suppositories is simple and as urologists there is a great deal of experience in the use of this medication for renal colic. The analgesic has local and general analgesic effects, and a low complication rate in select populations with no contraindication to nonsteroidal anti-inflammatory drugs. The suppositories were not visualized by the transrectal probes during the procedure because by 1 hour after administration they had dissolved. Our study shows no increased risk of infection or user variability. In addition, the administration of 1 suppository produces no potential long-term anatomical sequelae, as have been suggested with local anesthesia, and we would expect it to be equally beneficial in patients who have been treated with previous operative interventions to the prostate and for seminal vesicle biopsy. From this study we cannot state whether the decrease in pain scores was due to less discomfort from ultrasound probe insertion as well as needle passage. If so, the suppository would have a clear advantage over periprostatic lidocaine injection since injection has no effect on the pain felt during probe insertion. CONCLUSIONS

We believe that the administration of diclofenac suppositories 1 hour prior to TRUSP decreases patient discomfort associated with the procedure, improving patient tolerance without a significant increase in morbidity. The use of infiltration analgesia and diclofenac suppositories provides pain relief during prostatic biopsy and the choice of which to use depends on clinician preference. We believe that a placebo controlled comparison between the 2 types of analgesia would be interesting to determine which of the 2 alternatives would be most suitable. However, the important aspect is the provision of analgesia prior to prostate biopsy. We would urge urologists to introduce analgesia prior to TRUSP and biopsy into their practice due to the trend toward more core samples, screening for prostate cancer and the increasingly younger age of patients undergoing biopsy. REFERENCES

1. Crundwell, M. C., Cooke, P. W. and Wallace, D. M.: Patients’ tolerance of transrectal ultrasound— guided prostatic biopsy: an audit of 104 cases. BJU Int, 83: 792, 1999

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2. Irani, J., Fournier, F., Bon, D., Gremmo, E., Dore, B. and Aubert, J.: Patient tolerance of transrectal ultrasound-guided biopsy of the prostate. Br J Urol, 79: 608, 1997 3. Desgrandchamps, F., Meria, P., Irani, J., Desgrippes, A., Teillac, P. and Le Duc, A.: The rectal administration of lidocaine gel and tolerance of transrectal ultrasonography-guided biopsy of the prostate: a prospective randomized placebo-controlled study. BJU Int, 83: 1007, 1999 4. Peters, J. L., Thompson, J. C., McNicholas, T. A., Hines, J. E., Hanbury, D. C. and Boustead, G. B.: Increased patient satisfaction from transrectal ultrasonography and biopsy under sedation. BJU Int, 87: 827, 2001 5. Musood, J., Shah, N., Lane, T., Andrews, H., Simpson, P. and Barua, J.: Entonox inhalation and tolerance of transrectal ultrasound guided (TRUS) prostate biopsy: a double blind randomized controlled study. J Urol, suppl., 167: 332, abstract 1318, 2002 6. Soloway, M. S. and Obek, C.: Periprostatic local anaesthesia before ultrasound guided prostate biopsy. J Urol, 163: 172, 2000 7. Haq, A., Mattocks, S., Batstone, R. and Dawson, C. The role of analgesia in TRUSP and biopsy. BJU Int, suppl., 1: 134, 2000 8. Bossuyt, P. M., Reitsma, J. B., Bruns, D. E., Gatsonis, C. A., Glasziou, P. P., Irwig, L. M. et al: Towards complete and accurate reporting of studies of diagnostic accuracy: the STARD initiative. BMJ, 326: 41, 2003 9. Westenberg, A. M., Cossar, E. H., Lorimar, L. B. and Costello, J. P.: The acceptability of transrectal ultrasound guided prostate biopsy without anesthesia. N Z Med J, 112: 231, 1999 10. Rodriguez, L. V. and Terris, M. K.: Risks and complications of transrectal ultrasound guided prostate needle biopsy: a prospective study and review of the literature. J Urol, 160: 2115, 1998 11. Zisman, A., Leibovici, D., Kleinmann, J., Siegel, Y. I. and Lindner, A.: The impact of prostate biopsy on patient wellbeing: a prospective study of pain, anxiety and erectile dysfunction. J Urol, 165: 445, 2001 12. Wu, C. L., Carter, H. B., Naquibuddin, M. and Fleisher, L. A.: Effect of local anaesthetics on patient recovery after transrectal biopsy. Urology, 57: 925, 2001 13. Klein, E. A. and Zippe, C. D.: Editorial: transrectal ultrasound guided prostate biopsy— defining a new standard. J Urol, 163: 179, 2000 14. Seymour, H., Perry, M. J., Lee-Elliot, C., Dundas, D. and Patel, U.: Pain after transrectal ultrasonography-guided prostate biopsy: the advantages of periprostatic local anaesthesia. BJU Int, 88: 540, 2001