0022-5347/05/1742-0510/0 THE JOURNAL OF UROLOGY® Copyright © 2005 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 174, 510 –513, August 2005 Printed in U.S.A.
DOI: 10.1097/01.ju.0000165158.40132.e2
A RANDOMIZED, CONTROLLED TRIAL COMPARING LIDOCAINE PERIPROSTATIC NERVE BLOCK, DICLOFENAC SUPPOSITORY AND BOTH FOR TRANSRECTAL ULTRASOUND GUIDED BIOPSY OF PROSTATE N. RAGAVAN,* J. PHILIP, S. P. BALASUBRAMANIAN, J. DESOUZA, C. MARR
AND
P. JAVLE
From the Michael Heal Department of Urology, Leighton Hospital, Crewe and University of Sheffield (SPB), Sheffield, United Kingdom
ABSTRACT
Purpose: Lidocaine periprostatic nerve block (PPNB) provides good procedural pain relief for transrectal ultrasound (TRUS) prostatic biopsy. However, post-procedural pain can be significant. The addition of diclofenac suppository (DS) to lidocaine PPNB might provide additional, particularly post-procedural pain relief. We assessed the procedural and post-procedural pain relief for TRUS biopsy provided by DS, and the combination of DS and lidocaine PPNB compared with lidocaine PPNB alone. Materials and Methods: A total of 165 patients were randomized into 3 groups, namely group 1—lidocaine PPNB, group 2—DS and group 3—a combination of lidocaine PPNB and DS. In all patients 12 core biopsy was performed. Pain/discomfort at various intervals after the procedure was recorded on a visual analogue scale of 0 to 10 cm. Results: Biopsy pain was significantly lower in patients who received lidocaine alone or in combination compared with DS alone (median 1.95, IQR 1.08 to 3.12, 3, IQR 1.25 to 5.47 and 1.8, IQR 0.85 to 3.0, respectively, p ⫽ 0.018), while evening pain scores were significantly lower in patients who received DS alone or in combination compared with that in patients who received lidocaine alone (median 1.25, IQR 0.38 to 3.0, 0.3, IQR 0.03 to 1.08 and 0.4, IQR 0 to 1.0, respectively, p ⫽ 0.001). There were no significant differences in pain/discomfort due to the probe (p ⫽ 0.107), that 1 hour after biopsy (p ⫽ 0.076) and that on the day after the procedure (p ⫽ 0.165). There were no significant differences in hemorrhagic or infective complications among the groups. Conclusions: The combination of lidocaine PPNB with DS provides additional pain relief during and after prostatic TRUS biopsy. KEY WORDS: prostate; pain; biopsy; ultrasound, high-intensity focused, transrectal; lidocaine
Transrectal ultrasound (TRUS) guided biopsies of the prostate gland is the accepted mode of investigation for the diagnosis of prostate cancer. Irani et al reported that a significant number of patients refused to undergo the procedure again without any anesthesia.1 Studies have shown that lidocaine periprostatic block is a good form of anesthesia during the procedure2 and this is routinely used in our unit. However, patients have reported pain after the procedure and in the evening. Seymour et al reported that 9% or patients in the local anesthesia group and 14% in the nonlocal anesthesia group used additional analgesia.3 Diclofenac suppository (DS) has systemic anti-inflammatory and analgesic properties, and its addition to lidocaine periprostatic nerve block (PPNB) might provide additional benefit to patients to provide procedural and post-procedural pain relief. Diclofenac is absorbed rapidly and it attains a peak concentration in less than 40 minutes.4 It is useful for acute pain relief. Therefore, we performed a randomized, controlled clinical trial to compare the efficacy of 3 forms of analgesia, namely lidocaine PPNB and/or DS, for TRUS biopsy of the prostate. PATIENTS AND METHODS
Patients and selection criteria. During the 1-year period of June 2002 to May 2003 patients attending urology clinics at a
large district general hospital who were scheduled for TRUS biopsy of the prostate were considered for study inclusion. All patients had increased prostate specific antigen (PSA) with or without abnormal digital rectal examination. Patients on warfarin, those with a history of bleeding tendencies and those with known allergy to lidocaine or diclofenac were excluded from study. Informed consent was obtained from all who agreed to participate. One of us (NR) enrolled patients into the trial and randomly assigned them to treatment groups using sealed envelopes containing equal numbers of the 3 treatment arms. Group 1 patients received lidocaine PPNB only, group 2 patients received DS and group 3 patients received a combination of PPNB and DS. Ethical approval was obtained from the Local Research and Ethical Committee (LREC reference M176/02). A total of 165 patients were randomized into 3 groups of 55 each to receive lidocaine PPNB, DS or a combination of PPNB and DS. Antibiotic prophylaxis was administered with 500 mg ciprofloxacin twice daily starting on the day of the procedure and continued for the following 2 days. Technique. Any of the members of the urology team (NR, JD or PJ), who were experienced with the technique, performed biopsy. An ultrasound machine with a 7.5 MHz probe (Bruel and Kjaer, Decatur, Georgia) was used for the procedure. The periprostatic block was administered with 1% lidocaine using a 22 gauge spinal needle at the basolateral aspect of the gland using 10 ml per side. Although this is slightly more than what other studies have shown,2, 5 it was routine practice in the department and, therefore, it was also continued during the study. Gland dimensions were then
Submitted for publication November 8, 2004. Study received Local Research and Ethical Committee approval (LREC reference M176/02). * Correspondence: 39 Doveleys Rd., Salford, M6 7FT, United Kingdom (telephone and FAX: 0044 161 6616489; e-mail:
[email protected]). 510
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measured, thus, allowing few minutes for the local anesthesia to act prior to the actual procedure. Patients randomized to 100 mg DS alone or the combination were administered the drug at least 40 minutes before the proposed procedure. A total of 12 systematic prostatic cores, including 6 laterally targeted biopsies, in addition to conventional parasagittal biopsies covering the base, mid zones and apexes, were obtained in all patients with an 18 gauge cutting biopsy needle and spring loaded biopsy gun. All patients were observed for at least an hour after the procedure and they were discharged home only if they had voided successfully. Patients were discharged from the hospital with advice to ingest acetaminophen as necessary. Data collection. During the stay in the outpatient unit patients were counseled about the need to complete the questionnaire, which included a visual analogue pain score of 0 to 10 cm, regarding 1) pain/discomfort experienced due to the introduction and presence of the probe, 2) biopsy (pain felt due to the needle), 3) pain experienced an hour after the procedure, 4) pain later that evening and 5) pain the day after biopsy. Scores on the visual analogue scale were measured with a ruler. Patients also recorded possible complications and side effects. Specific questions, such as the need to visit a general practitioner or additional analgesia requirements, were also addressed in the questionnaire. A prepaid addressed envelope was provided for patients to return the questionnaire to the department. Statistical analysis. We calculated sample size requirements for 2 groups only. To compare the efficacy of diclofenac alone or combination of diclofenac with lidocaine vs the standard treatment of lidocaine only we calculated that 51 patients would be required per group to be able to detect a 1 cm difference in the visual analogue scale, assuming a mean of 1.6 and SD of 0.9 in the lidocaine group5 with a power of 80% and a type I error of 0.05. Data analysis was done by an external investigator (SPB) using SPSS for Windows, version 11.5 (SPSS, Chicago, Illinois). All continuous variables are described as the mean ⫾ SD if normally distributed and the median with the IQR if not normally distributed. Patient age was compared among the groups by ANOVA. Other variables, including pain scores, were compared using nonparametric tests, including the Kruskal-Wallis, chi-square or Fisher exact test as appropriate. Post hoc pairwise comparisons using the Mann-Whitney test were done if the pain scores were significantly different in the 3 groups, as shown by the Kruskal-Wallis test. Analysis was done according to the intent to treat principle. RESULTS
Of the 165 patients 147 returned the questionnaire (89% response). Table 1 lists the baseline characteristics of the 3 patient groups. The groups were similar with respect to patient age, PSA, prostate volume and the diagnosis of malignancy on TRUS biopsy. Table 2 shows the pain experienced by patients during and after the procedure. No significant differences were observed in pain scores due to the presence of the probe (p ⫽ 0.107), pain 1 hour after the procedure (p ⫽ 0.076) and pain the day following the procedure (p ⫽ 0.165). However, a significant difference among the groups was observed in pain noticed
due to biopsy (p ⫽ 0.018) and pain on the evening of the procedure (p ⫽ 0.001). Post hoc pairwise comparisons of biopsy pain and pain in the evening were done in the 3 groups using the Mann-Whitney U test. Biopsy pain scores were significantly lower in patients who received lidocaine PPNB alone (p ⫽ 0.03) or in combination (p ⫽ 0.008) compared with those who received DS alone. Pain scores on the evening of the procedure were found to be significantly lower in patients who received DS alone (p ⫽ 0.001) or in combination (p ⫽ 0.001) compared with that in patients who received lidocaine PPNB alone. Table 3 shows that 40%, 14.5% and 30.6% of the patients in groups 1 to 3, respectively, used analgesia within 3 days of the procedure. The questionnaire did not address the dose and amount of analgesia used by the patients. Patients in group 2 had minimal post-procedure analgesic use, which was statistically significant (chi-square test, 2 df, p ⫽ 0.019). The frequency of side effects, including hematuria, rectal bleeding, hemospermia and fever, in the 3 groups were not significantly different. Five patients needed post-procedure hospitalization. Two patients had clot retention, including 1 each in the lidocaine and diclofenac groups. One patient with rectal bleeding in the lidocaine group and 1 with fever in the diclofenac group also needed hospitalization but they were treated conservatively and discharged home the following day. One patient in acute urinary retention subsequently had a successful trial without a catheter after treatment with ␣-blockers. None of the patients had any acute allergic reactions to any of the drugs used in the study. DISCUSSION
The introduction of transrectal ultrasound guided biopsies by Torp-Pedersen et al,6 PSA guided early detection of prostate cancer and the availability of radical treatments for early prostate cancer has prompted groups at many centers to perform 12 core biopsy protocols. It is now established that a significant number of patients experience pain during and after prostate biopsy.7 Various pain relief modalities have been investigated, including lidocaine gel,8 entonox9 and PPNB. PPNB with lidocaine has been investigated by various groups and shown to be an effective form of anesthesia for biopsy.2, 5, 10 –12Lidocaine PPNB as a dominant form of analgesia became particularly popular after the study of Soloway and Obek.2 However, many patients report significant discomfort after the procedure and in the evening and, therefore, they routinely use analgesia. The prostate has a visceral nerve supply and, therefore, it is likely that the systemic anti-inflammatory and analgesic properties of diclofenac may help these patients. Diclofenac is available in oral, suppository and injectable forms. The suppository form is available as 100 mg and it gives effective pain relief for a long duration.4 We administered the medication at least 40 minutes before the procedure, allowing adequate time for it to act. We found that administering the drug was easy and did not pose any major increase in the staff workload. None of the patients who were randomized to receive DS refused the medication or expressed concern regarding the mode of drug administration. Because there were practical and financial difficulties with arranging placebo for DS and lidocaine injection, the study
TABLE 1. Baseline characteristics of 3 patient groups
No. pts Mean age ⫾ SD Median g/l PSA (IQR) Median ml prostate vol (IQR) No. Ca diagnosis
Lidocaine PPNB
Diclofenac Suppository
Combination
p Value
50 66.38 ⫾ 7.29 7.6 (5.17–10.65) 73.18 (56.30–94.10) 17
48 66.92 ⫾ 6.78 8.35 (5.80–12.90) 64.43 (52.0–96.77) 17
49 65.10 ⫾ 7.64 7.4 (5.0–12.05) 78.14 (58.07–98.43) 13
0.449 (ANOVA) 0.374 (Kruskal-Wallis test) 0.214 (Kruskal-Wallis test) 0.616 (Fisher’s exact test)
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LIDOCAINE NERVE BLOCK AND DICLOFENAC SUPPOSITORY FOR PROSTATE BIOPSY TABLE 2. Pain recorded on visual analogue scale in 3 groups Pain
Median Lidocaine PPNB (IQR)
Median Diclofenac Suppository (IQR)
Median Combination (IQR)
p Value (KruskalWallis test)
No. pts Probe Biopsy 1-Hr Evening Next day
50 1.95 (1.45–4.05) 1.95 (1.08–3.12) 1.05 (0.37–2.27) 1.25 (0.38–3.0) 0.35 (0–1.32)
48 3.0 (1.42–4.47) 3.0 (1.25–5.47) 0.6 (0.12–1.67) 0.3 (0.03–1.08) 0.2 (0–0.47)
49 2.0 (1.0–3.25) 1.8 (0.85–3.0) 0.5 (0–1.85) 0.4 (0–1.0) 0 (0–1.0)
0.107 0.018 0.076 0.001 0.165
TABLE 3. Other outcomes in 3 groups No. pts No. hematuria (%) Median days hematuria (IQR) No. rectal bleeding (%) Median days rectal bleeding (IQR) No. hemospermia (%) No. fever (%) No. hospitalization (%) No. general practitioner visit (%) No. analgesic used within 3 days (%)
Lidocaine PPNB
Diclofenac Suppository
Combination
p Value
50 43 (86) 3 (1–4) 23 (46) 0 (0–2) 13 (26) 1 (2) 2 (4) 0 20 (40)
48 40 (83.3) 1 (1–3) 21 (43.7) 0 (0–1) 16 (33.3) 2 (4.1) 2 (4.1) 0 7 (14.5)
49 38 (77.5) 2 (1–3) 24 (48.9) 0 (0–1) 13 (26.5) 0 1 (2) 1 (2) 15 (30.6)
0.531 (chi-square test) 0.107 (Fisher’s exact test) 0.874 (chi-square test) 0.740 (Kruskal-Wallis test) 0.672 (chi-square test) 0.322 (Fisher’s exact test) 0.871 (Fisher’s exact test) 0.660 (Fisher’s exact test) 0.019 (chi-square test)
was not blinded. We accept that this might have introduced bias in patient responses. All patients were counseled that they would be randomly allocated to 1 of 3 forms of analgesia. There were no differences in pain/discomfort scores due to introduction or presence of the probe and none of the agents seemed to be effective in this regard. It appears that pain due to biopsy is significantly helped by the use of lidocaine since scores recorded by patient groups 1 (lidocaine alone) and 3 (combination) were much lower than those in group 2 (diclofenac alone). Overall pain scores recorded an hour after the procedure were lower than that those of pain felt during biopsy. Of the 3 groups the combination group scores were lowest. However, this did not achieve statistical significance. Pain scores recorded the evening of the procedure in the combination and diclofenac alone groups were lower than those in the lidocaine alone group. This shows that patients with lidocaine alone had rebound pain in the evening and the difference between the groups was statically significant. It appears that DS with its long duration of action provided significant benefit in these patients. There were no differences in the pain scores recorded by patients on the day after the procedure. Overall pain scores recorded in the combination group were the least in all of the groups. The combination of PPNB with rectal diclofenac appears to provide the best form of pain relief. Although pain scores recorded on the day after the procedure were low with no differences among the groups, we still found that a number of patients used analgesia within 3 days of the procedure. Patients in the diclofenac alone group had the lowest analgesic use compared with the combination and lidocaine alone groups (14.6% vs 30.6% and 40%, respectively). It is difficult to explain higher analgesic use in the combination group compared with the group with diclofenac alone. This could have been a chance finding or lidocaine PPNB might have initiated an inflammatory reaction, therefore, necessitating increased analgesic use. It has been suggested that PPNB administration may result in postinflammatory fibrosis.13 Further studies are needed to specifically address the issues of longer term pain relief and analgesic use. We also acknowledge that the study is limited by the lack of blinding patients to the type of analgesia. We also did not stratify patients according to the individual performing the procedure since we believe that the learning process is short and the operator would be an unlikely factor influencing pain severity.
Crundwell et al reported post-procedural complications ex¨ bek et perienced before the use of periprostatic blocks7 and O al reported complications with periprostatic blocks.14 The incidence rates of bleeding related episodes in our series appear to be more than those reported in other published studies.14, 15 This may be due to the fact that patients were requested to record even minor amounts of hematuria/blood stained urine and the performance of standard 12 core biopsies in all patients. The duration of bleeding events in our series is comparable to that in another series, in which a combination of brief and long lasting anesthesia was used.16 At our hospital routine practice is to advise patients to contact the hospital directly instead of the general practitioner on the day of biopsy, which explains why we had 5 hospital admissions and only 1 patient who visited a general practitioner. There were no serious or life threatening hemorrhagic or infective complications in this study. Rebound pain after PPNB with lidocaine alone was addressed by Lee-Elliott et al.16 In a randomized trial comparing lidocaine vs lidocaine and bupivacaine (short and long acting drugs) periprostatic injections the group found that the combination significantly attenuated the 1-hour rebound pain seen after short acting anesthesia alone. Improved pain scores were also sustained during the subsequent week. Mean scores in patients in this study were 1 to 1.5 cm on the visual analogue scale with scores decreasing day by day after biopsy. There were no differences between the groups in analgesic use, although absolute values were not available. Oral rofecoxib, a nonsteroidal anti-inflammatory drug (NSAID), did not provide better pain relief than placebo for prostatic biopsies.17 Haq et al compared DS vs placebo as a single agent for prostatic biopsies in a randomized trial and found that rectal diclofenac provided better immediate relief than placebo.15 They did not address the issue of pain/discomfort felt on the evening or day after biopsy. To our knowledge there are no studies comparing lidocaine PPNB alone, DS alone and the combination after TRUS biopsy of the prostate. Overall pain scores recorded by our patients were lower compared to those in published studies, particularly in the post-procedural period. It may be argued that further decreases in pain provided by additional interventions may not be clinically significant. However, we believe that any degree of pain requiring analgesia should be addressed and DS, which is simple to administer and relatively safe, is helpful in this regard. The alternative option would be to ask the patient to take analgesia as and when necessary, which
LIDOCAINE NERVE BLOCK AND DICLOFENAC SUPPOSITORY FOR PROSTATE BIOPSY
can be acetaminophen or a NSAID depending on physician choice. We prefer to give a NSAID since this is an invasive procedure that is likely to induce some degree of inflammation. The option of DS before the procedure, as in this study, or an oral prescription should be the choice and preference of the patients and treating physicians. CONCLUSIONS
The combination of DS and lidocaine PPNB provides good additional pain relief during and after biopsy without any increased risk of complications. Pain scores recorded in this study are low. Although we would recommend routine use of this combination, it would be up to the patients and treating physicians to decide the strategy of post-procedural pain relief as routine pre-procedural diclofenac or a separate postprocedural prescription for pain relief. REFERENCES
1. 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 2. Soloway, M. S. and Obek, C.: Periprostatic local anesthesia before ultrasound guided prostate biopsy. J Urol, 163: 172, 2000 3. Seymour, H., Perry, M. J., Lee-Elliot, C., Dundas, D. and Patel, U.: Pain after transrectal ultrasonography guided biopsy: the advantages of periprostatic local anaesthesia. BJU Int, 88: 540, 2001 4. Ross, M. E., deVos, D., Guelen, P. J. M. and Janssen, T. J.: Pharmacokinetics of diclofenac enteric coated tablets and suppositories. Eur J Pharmacol, 183: 387, 1990 5. Nash, P. A., Bruce, J. E., Indudhara, R. and Shinohara, K.: Transrectal ultrasound guided prostatic nerve blockade eases systemic needle biopsy of the prostate. J Urol, 155: 607, 1996 6. Torp-Pedersen, S., Lee, F., Litturp, P. J., Siders, D. B., Kumasaka, G. H., Solomon, M. H. et al: Transrectal biopsy of the prostate guided with transrectal US: longitudinal and multiplanar scanning. Radiology, 170: 23, 1989 7. 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 8. 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 9. Srirangam, S. J., Manikandan, R. and Collins, G. N.: Efficacy of entonox vs. periprostatic infiltration of 1% lignocaine in providing analgesia during TRUS guided biopsy of the prostate. A prospective randomized controlled trial. BJU Int, 91: 48, abstract, 2003 10. Alavi, A. S., Soloway, M. S., Vaidya, A., Lynne, C. M. and Ghelier, E. L.: Local anaesthesia for ultrasound guided prostate biopsy: a prospective trial comparing 2 methods. J Urol, 166: 1343, 2001
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11. Lynn, N. N., Collins, G. N., Brown, S. C. and O’Reilly, P. H.: Periprostatic nerve block gives better analgesia for prostatic biopsy. BJU Int, 90: 424, 2002 12. Addla, S. K., Adeyoju, A. A., Wemyss-Holden, G. D. and Neilson, D.: Local anaesthetic for transrectal ultrasound-guided prostate biopsy: a prospective, randomized, double blind, placebocontrolled study. Eur Urol, 43: 441, 2003 13. Klein, E. A. and Zippe, C. D.: Editorial: transrectal ultrasound guided prostate biopsy— defining a new standard. J Urol, 163: 179, 2000 ¨ ¨ ¨ 14. Obek, C., Onal, B., Ozkan, B., Onder, A. U., Yalc¸in, V. and Solok, V.: Is periprostatic local anesthesia for transrectal ultrasound guided prostatic biopsy associated with increased infectious or hemorrhagic complications? A prospective randomized trial. J Urol, 168: 558, 2002 15. Haq, A., Patel, H. R. H., Habib, M. R., Donaldson, P. J. and Parry, J. R. W.: Diclofenac suppository analgesia for transrectal ultrasound guided biopsies of the prostate: a double blind, randomized controlled trial. J Urol, 171: 1489, 2004 16. Lee-Elliott, C. E., Dundas, D. and Patel, U.: Randomized trial of lidocaine vs lidocaine/bupivacaine periprostatic injection on longitudinal pain scores after prostate biopsy. J Urol, 171: 247, 2004 17. Moinzadeh, A., Mourtzinos, A., Triaca, V. and Hamawy, K. J.: A randomized double-blind prospective study evaluating patient tolerance of transrectal ultrasound-guided biopsy of the prostate using prebiopsy rofecoxib. Urology, 62: 1054, 2003 EDITORIAL COMMENT Several years ago (January 2001) we sent out a survey, which was completed by 88 urologists, and found that only 11% used PPNB in an effort to minimize the pain associated with TRUS guided biopsies of the prostate.1 A third did not prescribe anything to minimize pain. I would hope that the majority of those performing TRUS biopsies now use PPNB since a number of randomized trials, including the current report, indicate that this dramatically decreases pain. This is particularly important since most of us obtain 10 to 12 cores. These authors found that approximately a third of their patients receive additional oral analgesia after biopsy and they suggest that we should routinely prescribe a NSAID or similar analgesia to preempt this minor but annoying sequela. Although patients used to tolerate this anxiety provoking procedure without anesthesia, ie PPNB or other adequate anesthesia, that does not mean that we should be inconsiderate of their precarious position. Since reading this article, I will not only continue PPNB, but also will prescribe long acting analgesia to be received for 1 or 2 days after the procedure. Mark S. Soloway Department of Urology University of Miami School of Medicine Miami, Florida 1. Davis, M., Sofer, M., Kim, S. S. and Soloway, M. S.: The procedure of transrectal ultrasound guided biopsy of the prostate: a survey of patient preparation and biopsy technique. J Urol, 167: 566, 2002
