- Email: [email protected]
Diclofenac Suppository as a Preemptive Analgesia in Ultrasound-guided Biopsy of Prostate: Randomized Controlled Trial
Accepted Manuscript Diclofenac suppository as a preemptive analgesia in ultrasound guided biopsy of prostate: Randomized controlled trial Naveed Haroon, M Hammad Ather, Salma khan, Pirkash Kumar, Basit Salam PII:
S0090-4295(15)00499-9
DOI:
10.1016/j.urology.2015.04.044
Reference:
URL 19243
To appear in:
Urology
Received Date: 28 January 2015 Revised Date:
17 April 2015
Accepted Date: 21 April 2015
Please cite this article as: Haroon N, Ather MH, khan S, Kumar P, Salam B, Diclofenac suppository as a preemptive analgesia in ultrasound guided biopsy of prostate: Randomized controlled trial, Urology (2015), doi: 10.1016/j.urology.2015.04.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Original study: Diclofenac suppository as a preemptive analgesia in ultrasound guided
M Hammad Ather Salma khan Pirkash Kumar
Contact address:
M AN U
Basit Salam
SC
Naveed Haroon
RI PT
biopsy of prostate: Randomized controlled trial
Dr. M Hammad Ather, MD, FCPS (urol), FEBU Associate Prof and Director Urology residency Department of Surgery, Aga Khan University
Pakistan Tel.
[email protected]
AC C
Email:
+92 213 486 4778
EP
Karachi 74800
TE D
P.O. Box 3500, Stadium Road
Running title: Diclofenac suppository as preemptive analgesia in prostatic biopsy
Key words: Prostatic biopsy; Diclofenac suppository, pain score, Lidocaine, Xylocaine, visual analogue score (VAS). ACKNOWLEDGEMENTS We would like to acknowledge all urology residents for their support during the study and Dr. Ghulam Murtaza for his constant support in statistical analysis.
ACCEPTED MANUSCRIPT ABSTRACT Objective
To
compare
pre-procedure
Diclofenac
suppository
and
Xylocaine gel with Xylocaine gel only in patients undergoing trans rectal
Methods
RI PT
ultrasound (TRUS) guided biopsy of prostate for pain. It is a randomized controlled trial conducted on patients
undergoing TRUS guided biopsy for clinical or biochemical suspicion of prostate cancer following a written informed consent and ERC approval.
SC
Patients were randomized in two groups. Group A included those patients
M AN U
who received Diclofenac suppository 2 hours before in combination with 10 ml of 2% Xylocaine gel 5 minutes before biopsy. Group B received Xylocaine gel only. A visual analog scale was used to measure the pain scores at the time of TRUS probe insertion, just after taking biopsy cores and 2 hours after biopsy.
A total of 100 patients were recruited in the study with 50
TE D
Results
patients each in Group A and B. Mean age of Group A was 69.1±10 years
EP
and 67.3±8.1 years for Group B. The mean pain score for group A and B at the time of probe insertion was 0.08+0.27 and 0.34+0.63 (p= 0.032),
AC C
immediately after taking biopsy cores was 1.46+1.15 and 4.68+0.77 (p 0.000) and 2 hours after biopsy was 0.14+0.45 versus 2.40+0.81(p 0.000) respectively.
Conclusion The mean pain score at the time of TRUS probe insertion, immediately after taking biopsy cores and 2 hours after biopsy is statistically significantly higher in-group B.
ACCEPTED MANUSCRIPT
INTRODUCTION Transrectal ultrasound (TRUS)-guided prostate biopsy is a commonly performed
RI PT
procedure for the diagnosis of prostate cancer. Pain is one of the common side effects of this procedure and it is noted that a third of patients required self-medicated
SC
analgesia post-procedure1.
Discomfort and pain during TRUS guided prostatic biopsy received little attention until
M AN U
recently. The procedure related pain has two components; one occurs at the insertion of ultrasound probe into the rectum and the other is due to needle punctures during biopsy. The pain is mediated by C fibers that are richly present in the autonomic nerve fibers in the peri prostatic area. There are local inflammatory mediators that augment this pain, which adds to the local edema. The pain due to the introduction and
TE D
movements of the TRUS guided probe into the rectum and needle passage through the prostate capsule during biopsy course. This is augmented by several other reasons
EP
such as fear of the potential diagnosis of cancer and anal route of penetration by the TRUS guided probe. However, recently use of anxiolytics prior to biopsy was assessed
AC C
and authors2 noted that Diazepam does not improve patient pain perception immediately after or at one-week recall following prostate biopsy. Patient positioning is also considered important3. Lateral decubitus position is preferred over lithotomy position3.
Peri prostatic injection of local anaesthetic agents around the prostatic nerve bundles during TRUS biopsy of the prostate has shown to reduce the pain associated with the Page 1
ACCEPTED MANUSCRIPT
procedure. However, its position as the current gold standard is being challenged by many recent publications indicating additional analgesia provides better pain control than nerve block alone. The combination of periprostatic nerve blockade and intrarectal
RI PT
lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel4. Recently it has been noted that additional use of lidocaie-prilocaine jel in addition to peri prostatic nerve block provides better analgesia It has been shown that some of the discomfort
SC
in a randomized controlled trail5.
associated with the procedure is secondary to spasm of the anal sphincter. Jindal and
M AN U
colleagues6 used diltiazem as an adjunct to local anaesthetic in TRUS biopsy of the prostate, the presence of the probe, pain during the biopsy and overall pain prior to leaving the department, mean VAS was higher for the placebo group, but the difference
TE D
was not statistically significant.
The rationale of the current work is to find out the role and efficacy of rectal administration of Diclofenac suppository as an adjunct to 2% Xylocaine gel in alleviating
AC C
EP
intra and post procedural pain in prostatic biopsy.
Page 2
ACCEPTED MANUSCRIPT
MATERIALS AND METHODS
RI PT
It was a randomized controlled trial, which was done in the radiology department of a University Hospital from July 2011 to December 2011. Formal Ethics Review Committee (ERC) approval was taken vide reference no 1865-ERC-SUR-11 followed by acquisition
SC
of an approval from the clinical trail unit of the university. Trial is registered with clinical trials (Clinical Trials.gov NCT01939743). An informed consent was obtained from all
M AN U
participants.
The sample size was 50 patients in each arm (Figure 1). Sample size was determined on WHO software while taking the values of VAS of Diclofenac vs. placebo (2.8 ± 2.28 vs. 4.9± 2.29) (13). At 3% level of significance and 99% power, a sample of 50 patients
TE D
in each intervention arm was required. The inclusion criteria included those patients with raised PSA level of > 4.0 ng/ml with palpable nodularity on DRE or those patients who
EP
had palpable nodularity without high PSA.
Those patients who had echoic lesion
compared to surrounding prostate on TRUS along with either raised PSA or palpable Those patients who had anal pathologies and
AC C
nodularity, alone or in combination.
prostatic pathologies and those with history of previous biopsies, concomitant analgesic medication, chronic renal failure and allergy to Diclofenac were excluded from the study. Data collection was done on a Performa. The patients were randomized in two groups. Group A received 100 mg of Diclofenac suppository 1 hour before the biopsy followed by 5 ml of 2% Xylocaine gel 5 minutes before the procedure. Group B received only 5 ml of 2% Xylocaine gel 5 minutes before the procedure. Patients were put on oral Page 3
ACCEPTED MANUSCRIPT
quinolones 24 hours before the procedure and it was followed on up to 2-3 days after the procedure along with pre-procedural IV Amikacin as well. Patients in both the groups were similarly positioned i.e. in the left lateral position. A 2 cm, 18 gauge, Tru-
RI PT
Cut biopsy needle was used under TRUS guidance. The procedure was done by an interventional radiologist with more than 5 years’ experience of TRUS guided biopsies. Sextant or octant core biopsy was followed as depicted in the picture. The referring Visual analogue score was explained before the
SC
urologist decided the scheme.
procedure and pain was measured at the time of insertion of ultrasound probe, after
M AN U
taking all the biopsy cores and 2 hours thereafter. No pain was designated as 0 and unbearable pain as 10. It was recorded on the Performa by a trained registered nurse or principal investigator in a biopsy suite.
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Age and visual analogue score were described as mean and standard deviation. Comorbids were analyzed as proportion and percentages. Student t-test was used for comparison of pain scores. Stratified analysis was also done for age, comorbids and
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EP
biopsy scheme.
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RESULTS There was no statistical difference between the two groups in the baseline variables
RI PT
(Table 1). Most of the patients received sextant biopsies followed by octant scheme. The pain scores between the two groups, at all three instances the pain score was statistically significant between the two groups (Figure 2) i.e. at the time of probe
SC
insertion, immediately after taking biopsy cores and 2 hours after biopsy (Table 2).
M AN U
The stratified analysis to assess correlation of pain score (at probe insertion, completion of biopsy and 2 hours following biopsy) with age, comorbids or biopsy scheme was performed. Comparison of the mean using student t test of pain with age (<65 years and >65 years) showed no statistically significant difference. Comparison of the mean pain score with the presence and otherwise of the various comorbid conditions also showed
TE D
no significant difference. Pain score with octant and sextant biopsy with pain at the time of probe insertion; completion of biopsy and 2 hours following biopsy was also not
EP
statistically different (p 0.264, 0.046 and 0335) respectively. Three patients in group A and two in group B complained on transient hematuria (overt), which got better on its
AC C
own. One patient in each group complained on hematochezia lasting two days.
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DISCUSSION
RI PT
Various modalities have been studied till date in order to diminish this pain. Controversy exists over the ideal way of control pain during TRUS guided biopsy. Peri prostatic nerve block is currently considered as a gold standard. Recent studies have
SC
however, showed that periprostatic nerve block (PPNB) alone is insufficient as analgesia during the procedure7. It has been shown that some of the discomfort
M AN U
associated with the procedure is secondary to spasm of the anal sphincter. Topical diltiazem can relax the anal sphincter. Jindal et al6, however, recently reported no superiority of diltiazem over placebo. PPNB provides good pain control in TRUS-guided prostate biopsy but still there is often a need of additional analgesia. Kumar and colleague7 compared the efficacy of tramadol and intraprostatic nerve block (INB) in
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addition to PPNB. They noted that VAS score was statistically significantly better in the groups with additional analgesia in the form of oral Tramadol or INB. They also
EP
observed that Tramadol has advantage of oral intake and analgesic effect at time of probe insertion and at nerve block. Both tramadol and INB may be used in combination
AC C
along with PPNB. The present study aims to assess the efficacy of Diclofenac suppository to alleviate the pain related to TRUS guided biopsy of prostate. In the current work only sextant and octant biopsies were obtained, as this was the prevalent practice at that time in our institution. For prostate volume 30-40 mL, > 8 cores should be sampled. Ten to 12 core biopsies are recommended8, with > 12 cores not being significantly more conclusive
Page 6
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In order to decrease probe related discomfort various modalities have been tried. It includes intra rectal administration of Lidocaine gel, Lidocaine Prilocaine cream (EMLA cream) and Lidocaine suppositories before the procedure.
Anup and colleagues5
RI PT
recently showed that The combination of perianal-intra rectal lidocaine-prilocaine and PPNB provides better analgesia, especially in patients <60 years, prostate volume >50 cc and lower anorectal compliance as compared to two modalities used alone during
SC
the sampling part of TRUS guided prostate biopsy with no increase in the complication rate. Our results indicate that use of diclofenac suppository improved painful sensations
M AN U
as reported by the patient significantly compared to the control in all the three arms of study. Irer et al9 in a randomized trail between Diclofenac suppository and Lidocaine gel with glycerine suppository and Lidocaine gel in 40 patients noted that Intrarectal diclofenac suppository administration is a simple, safe, and effective procedure to
TE D
reduce pain and improve patients' tolerance of transrectal ultrasound-guided prostate biopsy. However, authors noted pain scores only at one instance i.e. immediately after biopsy, which was comparatively higher than in our study. Ragavan et al10 randomized
EP
patients into three groups i.e. periporstatic nerve block, diclofenac suppository and combination of the two. They noted that the combination of lidocaine PPNB with DS
AC C
provides additional pain relief during and after prostatic TRUS biopsy.
Another modality described over a decade back is pudendal nerve block11. Authors’ noted a statistically significant difference in pain scores when patients were given a unilateral pudendal blockade with 10 mg of 1% Prilocaine mixed with 10 ml of normal saline.
The main limitation of this technique is that it needed expertise and often
ultrasound was needed for difficult cases. Page 7
ACCEPTED MANUSCRIPT
However, there had not been any further work in this area. The more popular nerve block technique is periprostatic nerve block. It has been extensively studied and is now
RI PT
regarded as the current gold standard. However, still there is no agreement on the dosage of anesthetic and the technique of the block. There is also a large question mark on its pain reduction while probe introduction and manipulation into the rectum.
SC
Other agents tested so far are oral Rofecoxib, oral Morphine and IM Diclofenac but up till now these drugs compared to controls in the following studies have showed no
M AN U
statistical difference. Recently Canitello et al12 showed that the pelvic plexus block under Doppler ultrasound guidance provides better analgesia than periprostatic nerve block during office based transrectal ultrasound guided prostate biopsy.
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Diclofenac Sodium is a commonly used as a local and systemic anti-inflammatory drug, which reduces local mediators.
Its maximal plasma level is in 1-2 hours and is
maintained up to 12 hours. Diclofenac suppository offers a more practical option in
EP
terms of its non-invasiveness; registered nurse in those facilities can administer it, its wide availability and it where expertise is lacking for peri prostatic nerve block. Haq et
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al noted13 that 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.
The strengths of our study were that it has adequate sample size, pain score was measured at strategically correct timings and there was pre-procedural counseling after the procedure. The patients were properly counseled about before the induction about Page 8
ACCEPTED MANUSCRIPT
the VAS In previous studies. The major limitations of the study was lack of double blinding and patient with sextant and octant biopsy were only included.
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CONCLUSION Mean pain at the time of ultrasound probe insertion, immediately after and two hours after the procedure was significantly lower in patients undergoing TRUS guided biopsy
SC
with prior administration of Diclofenac suppository and Xylocaine gel as compared to
M AN U
Xylocaine gel alone.
Figure legend Figure 1
Flow diagram of the progress through the phases of RCT (Consort
statement)
The mean pain score, assessed by a visual analogue scale (range 0 = no
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Figure 2:
AC C
EP
pain to 10=unbearable pain) immediately after probe insertion, biopsy and at 2 hours.
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References
1
Ubee SS1, Marri RR, Srirangam SJ. Pain related and overall morbidity with TRUS guided prostate biopsy--a prospective study. Int Braz J Urol. 2013 Sep-Oct;39(5):671-4.
2
RI PT
Li R, Ruckle HC, Creech J, Culpepper D, Lightfoot M, Alsyouf M, Nicolay LI, Jellison F, Baldwin DD. A Prospective Randomized Controlled Trial Assessing Diazepam to Reduce Perception and Recall of Pain During Transrectal Ultrasound Guided Biopsy of the Prostate. J
Endourol. 2014 Jul;28(7):881-6. 3
SC
Kilciler M1, Demir E, Bedir S, Erten K, Kilic C, Peker AF. Pain scores and early complications of transrectal ultrasonography-guided prostate biopsy: effect of patient position. Urol Int. 2007;79(4):361-3. 4
M AN U
Otunctemur A1, Dursun M, Besiroglu H, Can Polat E, Cakir SS, Ozbek E, Karadeniz T. The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy. Arch Ital Urol Androl. 2013 Jun 24;85(2):69-72. doi: 10.4081/aiua.2013.2.69.
5
Anup K1, Pawan V, Niraj K, Biswajit N, Nayan MK. A prospective randomized trial comparing three different analgesic techniques for pain control during transrectal ultrasound guided prostate biopsy: a single center experience. Minerva Urol Nefrol. 2013 Mar;65(1):77-82.
6
7
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Jindal T, Mandal SN, Biswas G, Karmakar D.Evaluation of the efficacy of a combination of diltiazem and periprostatic nerve block in pain control during transrectal ultrasonography-guided biopsy of the prostate. Ann R Coll Surg Engl. 2013 Jul;95(5):361-4.
8
EP
Kumar A1, Griwan MS, Singh SK, Sen J, Pawar DS. Is periprostatic nerve block a gold standard in case of transrectal ultrasound-guided prostate biopsy? Urol Ann. 2013 Jul;5(3):152-6. doi: 10.4103/0974-7796.115732.
9
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Eichler K, Hempel S, Wilby J, et al. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol 2006 May;175(5):1605-12. Irer B, Gulcu A, Aslan G, Goktay Y, Celebi I. Diclofenac suppository administration in conjunction with lidocaine gel during transrectal ultrasound-guided prostate biopsy: prospective, randomized, placebo-controlled study. Urology. 2005 Oct;66(4):799-802.
10
Ragavan N, Philip J, Balasubramanian SP, Desouza J, Marr C, Javle P. A randomized, controlled trial comparing lidocaine periprostatic nerve block, diclofenac suppository and both for transrectal ultrasound guided biopsy of prostate. J Urol. 2005 Aug;174(2):510-3; discussion 513.
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11
Adsan O, Inal G, Ozdoğan L, Kaygisiz O, Uğurlu O, Cetinkaya M. Unilateral pudendal nerve blockade for relief of all pain during transrectal ultrasound-guided biopsy of the prostate: a randomized, double-blind, placebo-controlled study. Urology. 2004 Sep;64(3):528-31. 12
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Cantiello F, Cicione A, Autorino R, Cosentino C, Amato F, Damiano R. Pelvic plexus block is more effective than periprostatic nerve block for pain control during office transrectal ultrasound guided prostate biopsy: a single center, prospective, randomized, double arm study. J Urol. 2012 Aug;188(2):417-21.
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Haq A, Patel HR, Habib MR, Donaldson PJ, Parry JR. Diclofenac suppository analgesia for transrectal ultrasound guided biopsies of the prostate: a double-blind, randomized controlled trial. J Urol. 2004 Apr;171(4):1489-91.
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ACCEPTED MANUSCRIPT COMPARISON OF BASELINE VARIABLES Group A Group B (n=50) (n=50)
Comorbid Yes No
32 (64%) 18 (36%)
Diabetes Yes No
14 (28%) 36 (72%)
Hypertension Yes No Ischemic heart disease Yes No
34 (68%) 16 (32%)
0.2352
0.4173
15 (30%) 35 (70%)
0.5003
24 (48%) 26 (52%)
26 (52%) 24 (48%)
0.4213
8 (16%) 42 (84%)
9 (18%) 41 (82%)
0.5003
46 (92%) 4 (8%)
0.3453
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43 (86%) 7 (14%)
EP
Biopsy Sextant Extended
67.3±8.08
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69.1±10.01
p-value
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Age in years1
SC
Table 1 Variables
AC C
1 Mean±Standard deviation, 2 Student’s t-test, 3 Chi square tests
ACCEPTED MANUSCRIPT Table 2
COMPARISONS OF PAIN SCORE BETWEEN THE GROUPS Pain score (mean SD)
Time
p-value
Immediately after taking biopsy cores
1.46±1.146
2 hours after biopsy
0.14±0.450
TE D EP AC C
0.34±0.626
0.032
4.68±0.767
0.000
2.40±0.808
0.000
SC
0.08±0.274
M AN U
At the time of probe insertion
Group B
RI PT
Group A
RI PT
ACCEPTED MANUSCRIPT
Enrollment
M AN U
SC
Assessed for eligibility (n=113)
Excluded (n= 13) ♦ painful anorectal condition (n= 6 ) ♦ prostatitis (n=4 ) ♦ allergy to diclofenac (n= 3)
Randomized (n= 100)
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Allocation Allocated to lidocaine suppository alone (n=50)
Follow-Up
AC C
EP
Allocated to Diclofenac suppository and lidocaine jel group (n=50)
Lost to follow-up (n=0 )
Lost to follow-up (n= 0) Discontinued intervention (give reasons) (n= )
Analysis Analysed (n= 50)
Analysed (n= 50)
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ACCEPTED MANUSCRIPT
Treatment arms
AC C
EP
TE D
M AN U
SC
…………Lidocaine jelly only group
_____ Lidocaine jelly + Diclofenac suppository
S0090-4295(15)00499-9
DOI:
10.1016/j.urology.2015.04.044
Reference:
URL 19243
To appear in:
Urology
Received Date: 28 January 2015 Revised Date:
17 April 2015
Accepted Date: 21 April 2015
Please cite this article as: Haroon N, Ather MH, khan S, Kumar P, Salam B, Diclofenac suppository as a preemptive analgesia in ultrasound guided biopsy of prostate: Randomized controlled trial, Urology (2015), doi: 10.1016/j.urology.2015.04.044. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Original study: Diclofenac suppository as a preemptive analgesia in ultrasound guided
M Hammad Ather Salma khan Pirkash Kumar
Contact address:
M AN U
Basit Salam
SC
Naveed Haroon
RI PT
biopsy of prostate: Randomized controlled trial
Dr. M Hammad Ather, MD, FCPS (urol), FEBU Associate Prof and Director Urology residency Department of Surgery, Aga Khan University
Pakistan Tel.
[email protected]
AC C
Email:
+92 213 486 4778
EP
Karachi 74800
TE D
P.O. Box 3500, Stadium Road
Running title: Diclofenac suppository as preemptive analgesia in prostatic biopsy
Key words: Prostatic biopsy; Diclofenac suppository, pain score, Lidocaine, Xylocaine, visual analogue score (VAS). ACKNOWLEDGEMENTS We would like to acknowledge all urology residents for their support during the study and Dr. Ghulam Murtaza for his constant support in statistical analysis.
ACCEPTED MANUSCRIPT ABSTRACT Objective
To
compare
pre-procedure
Diclofenac
suppository
and
Xylocaine gel with Xylocaine gel only in patients undergoing trans rectal
Methods
RI PT
ultrasound (TRUS) guided biopsy of prostate for pain. It is a randomized controlled trial conducted on patients
undergoing TRUS guided biopsy for clinical or biochemical suspicion of prostate cancer following a written informed consent and ERC approval.
SC
Patients were randomized in two groups. Group A included those patients
M AN U
who received Diclofenac suppository 2 hours before in combination with 10 ml of 2% Xylocaine gel 5 minutes before biopsy. Group B received Xylocaine gel only. A visual analog scale was used to measure the pain scores at the time of TRUS probe insertion, just after taking biopsy cores and 2 hours after biopsy.
A total of 100 patients were recruited in the study with 50
TE D
Results
patients each in Group A and B. Mean age of Group A was 69.1±10 years
EP
and 67.3±8.1 years for Group B. The mean pain score for group A and B at the time of probe insertion was 0.08+0.27 and 0.34+0.63 (p= 0.032),
AC C
immediately after taking biopsy cores was 1.46+1.15 and 4.68+0.77 (p 0.000) and 2 hours after biopsy was 0.14+0.45 versus 2.40+0.81(p 0.000) respectively.
Conclusion The mean pain score at the time of TRUS probe insertion, immediately after taking biopsy cores and 2 hours after biopsy is statistically significantly higher in-group B.
ACCEPTED MANUSCRIPT
INTRODUCTION Transrectal ultrasound (TRUS)-guided prostate biopsy is a commonly performed
RI PT
procedure for the diagnosis of prostate cancer. Pain is one of the common side effects of this procedure and it is noted that a third of patients required self-medicated
SC
analgesia post-procedure1.
Discomfort and pain during TRUS guided prostatic biopsy received little attention until
M AN U
recently. The procedure related pain has two components; one occurs at the insertion of ultrasound probe into the rectum and the other is due to needle punctures during biopsy. The pain is mediated by C fibers that are richly present in the autonomic nerve fibers in the peri prostatic area. There are local inflammatory mediators that augment this pain, which adds to the local edema. The pain due to the introduction and
TE D
movements of the TRUS guided probe into the rectum and needle passage through the prostate capsule during biopsy course. This is augmented by several other reasons
EP
such as fear of the potential diagnosis of cancer and anal route of penetration by the TRUS guided probe. However, recently use of anxiolytics prior to biopsy was assessed
AC C
and authors2 noted that Diazepam does not improve patient pain perception immediately after or at one-week recall following prostate biopsy. Patient positioning is also considered important3. Lateral decubitus position is preferred over lithotomy position3.
Peri prostatic injection of local anaesthetic agents around the prostatic nerve bundles during TRUS biopsy of the prostate has shown to reduce the pain associated with the Page 1
ACCEPTED MANUSCRIPT
procedure. However, its position as the current gold standard is being challenged by many recent publications indicating additional analgesia provides better pain control than nerve block alone. The combination of periprostatic nerve blockade and intrarectal
RI PT
lidocain gel provides a more meaningful pain relief compared to group of patients undergoing intrarectal lidocaine gel4. Recently it has been noted that additional use of lidocaie-prilocaine jel in addition to peri prostatic nerve block provides better analgesia It has been shown that some of the discomfort
SC
in a randomized controlled trail5.
associated with the procedure is secondary to spasm of the anal sphincter. Jindal and
M AN U
colleagues6 used diltiazem as an adjunct to local anaesthetic in TRUS biopsy of the prostate, the presence of the probe, pain during the biopsy and overall pain prior to leaving the department, mean VAS was higher for the placebo group, but the difference
TE D
was not statistically significant.
The rationale of the current work is to find out the role and efficacy of rectal administration of Diclofenac suppository as an adjunct to 2% Xylocaine gel in alleviating
AC C
EP
intra and post procedural pain in prostatic biopsy.
Page 2
ACCEPTED MANUSCRIPT
MATERIALS AND METHODS
RI PT
It was a randomized controlled trial, which was done in the radiology department of a University Hospital from July 2011 to December 2011. Formal Ethics Review Committee (ERC) approval was taken vide reference no 1865-ERC-SUR-11 followed by acquisition
SC
of an approval from the clinical trail unit of the university. Trial is registered with clinical trials (Clinical Trials.gov NCT01939743). An informed consent was obtained from all
M AN U
participants.
The sample size was 50 patients in each arm (Figure 1). Sample size was determined on WHO software while taking the values of VAS of Diclofenac vs. placebo (2.8 ± 2.28 vs. 4.9± 2.29) (13). At 3% level of significance and 99% power, a sample of 50 patients
TE D
in each intervention arm was required. The inclusion criteria included those patients with raised PSA level of > 4.0 ng/ml with palpable nodularity on DRE or those patients who
EP
had palpable nodularity without high PSA.
Those patients who had echoic lesion
compared to surrounding prostate on TRUS along with either raised PSA or palpable Those patients who had anal pathologies and
AC C
nodularity, alone or in combination.
prostatic pathologies and those with history of previous biopsies, concomitant analgesic medication, chronic renal failure and allergy to Diclofenac were excluded from the study. Data collection was done on a Performa. The patients were randomized in two groups. Group A received 100 mg of Diclofenac suppository 1 hour before the biopsy followed by 5 ml of 2% Xylocaine gel 5 minutes before the procedure. Group B received only 5 ml of 2% Xylocaine gel 5 minutes before the procedure. Patients were put on oral Page 3
ACCEPTED MANUSCRIPT
quinolones 24 hours before the procedure and it was followed on up to 2-3 days after the procedure along with pre-procedural IV Amikacin as well. Patients in both the groups were similarly positioned i.e. in the left lateral position. A 2 cm, 18 gauge, Tru-
RI PT
Cut biopsy needle was used under TRUS guidance. The procedure was done by an interventional radiologist with more than 5 years’ experience of TRUS guided biopsies. Sextant or octant core biopsy was followed as depicted in the picture. The referring Visual analogue score was explained before the
SC
urologist decided the scheme.
procedure and pain was measured at the time of insertion of ultrasound probe, after
M AN U
taking all the biopsy cores and 2 hours thereafter. No pain was designated as 0 and unbearable pain as 10. It was recorded on the Performa by a trained registered nurse or principal investigator in a biopsy suite.
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Age and visual analogue score were described as mean and standard deviation. Comorbids were analyzed as proportion and percentages. Student t-test was used for comparison of pain scores. Stratified analysis was also done for age, comorbids and
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biopsy scheme.
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RESULTS There was no statistical difference between the two groups in the baseline variables
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(Table 1). Most of the patients received sextant biopsies followed by octant scheme. The pain scores between the two groups, at all three instances the pain score was statistically significant between the two groups (Figure 2) i.e. at the time of probe
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insertion, immediately after taking biopsy cores and 2 hours after biopsy (Table 2).
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The stratified analysis to assess correlation of pain score (at probe insertion, completion of biopsy and 2 hours following biopsy) with age, comorbids or biopsy scheme was performed. Comparison of the mean using student t test of pain with age (<65 years and >65 years) showed no statistically significant difference. Comparison of the mean pain score with the presence and otherwise of the various comorbid conditions also showed
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no significant difference. Pain score with octant and sextant biopsy with pain at the time of probe insertion; completion of biopsy and 2 hours following biopsy was also not
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statistically different (p 0.264, 0.046 and 0335) respectively. Three patients in group A and two in group B complained on transient hematuria (overt), which got better on its
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own. One patient in each group complained on hematochezia lasting two days.
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DISCUSSION
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Various modalities have been studied till date in order to diminish this pain. Controversy exists over the ideal way of control pain during TRUS guided biopsy. Peri prostatic nerve block is currently considered as a gold standard. Recent studies have
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however, showed that periprostatic nerve block (PPNB) alone is insufficient as analgesia during the procedure7. It has been shown that some of the discomfort
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associated with the procedure is secondary to spasm of the anal sphincter. Topical diltiazem can relax the anal sphincter. Jindal et al6, however, recently reported no superiority of diltiazem over placebo. PPNB provides good pain control in TRUS-guided prostate biopsy but still there is often a need of additional analgesia. Kumar and colleague7 compared the efficacy of tramadol and intraprostatic nerve block (INB) in
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addition to PPNB. They noted that VAS score was statistically significantly better in the groups with additional analgesia in the form of oral Tramadol or INB. They also
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observed that Tramadol has advantage of oral intake and analgesic effect at time of probe insertion and at nerve block. Both tramadol and INB may be used in combination
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along with PPNB. The present study aims to assess the efficacy of Diclofenac suppository to alleviate the pain related to TRUS guided biopsy of prostate. In the current work only sextant and octant biopsies were obtained, as this was the prevalent practice at that time in our institution. For prostate volume 30-40 mL, > 8 cores should be sampled. Ten to 12 core biopsies are recommended8, with > 12 cores not being significantly more conclusive
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In order to decrease probe related discomfort various modalities have been tried. It includes intra rectal administration of Lidocaine gel, Lidocaine Prilocaine cream (EMLA cream) and Lidocaine suppositories before the procedure.
Anup and colleagues5
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recently showed that The combination of perianal-intra rectal lidocaine-prilocaine and PPNB provides better analgesia, especially in patients <60 years, prostate volume >50 cc and lower anorectal compliance as compared to two modalities used alone during
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the sampling part of TRUS guided prostate biopsy with no increase in the complication rate. Our results indicate that use of diclofenac suppository improved painful sensations
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as reported by the patient significantly compared to the control in all the three arms of study. Irer et al9 in a randomized trail between Diclofenac suppository and Lidocaine gel with glycerine suppository and Lidocaine gel in 40 patients noted that Intrarectal diclofenac suppository administration is a simple, safe, and effective procedure to
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reduce pain and improve patients' tolerance of transrectal ultrasound-guided prostate biopsy. However, authors noted pain scores only at one instance i.e. immediately after biopsy, which was comparatively higher than in our study. Ragavan et al10 randomized
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patients into three groups i.e. periporstatic nerve block, diclofenac suppository and combination of the two. They noted that the combination of lidocaine PPNB with DS
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provides additional pain relief during and after prostatic TRUS biopsy.
Another modality described over a decade back is pudendal nerve block11. Authors’ noted a statistically significant difference in pain scores when patients were given a unilateral pudendal blockade with 10 mg of 1% Prilocaine mixed with 10 ml of normal saline.
The main limitation of this technique is that it needed expertise and often
ultrasound was needed for difficult cases. Page 7
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However, there had not been any further work in this area. The more popular nerve block technique is periprostatic nerve block. It has been extensively studied and is now
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regarded as the current gold standard. However, still there is no agreement on the dosage of anesthetic and the technique of the block. There is also a large question mark on its pain reduction while probe introduction and manipulation into the rectum.
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Other agents tested so far are oral Rofecoxib, oral Morphine and IM Diclofenac but up till now these drugs compared to controls in the following studies have showed no
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statistical difference. Recently Canitello et al12 showed that the pelvic plexus block under Doppler ultrasound guidance provides better analgesia than periprostatic nerve block during office based transrectal ultrasound guided prostate biopsy.
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Diclofenac Sodium is a commonly used as a local and systemic anti-inflammatory drug, which reduces local mediators.
Its maximal plasma level is in 1-2 hours and is
maintained up to 12 hours. Diclofenac suppository offers a more practical option in
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terms of its non-invasiveness; registered nurse in those facilities can administer it, its wide availability and it where expertise is lacking for peri prostatic nerve block. Haq et
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al noted13 that 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.
The strengths of our study were that it has adequate sample size, pain score was measured at strategically correct timings and there was pre-procedural counseling after the procedure. The patients were properly counseled about before the induction about Page 8
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the VAS In previous studies. The major limitations of the study was lack of double blinding and patient with sextant and octant biopsy were only included.
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CONCLUSION Mean pain at the time of ultrasound probe insertion, immediately after and two hours after the procedure was significantly lower in patients undergoing TRUS guided biopsy
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with prior administration of Diclofenac suppository and Xylocaine gel as compared to
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Xylocaine gel alone.
Figure legend Figure 1
Flow diagram of the progress through the phases of RCT (Consort
statement)
The mean pain score, assessed by a visual analogue scale (range 0 = no
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Figure 2:
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pain to 10=unbearable pain) immediately after probe insertion, biopsy and at 2 hours.
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References
1
Ubee SS1, Marri RR, Srirangam SJ. Pain related and overall morbidity with TRUS guided prostate biopsy--a prospective study. Int Braz J Urol. 2013 Sep-Oct;39(5):671-4.
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Li R, Ruckle HC, Creech J, Culpepper D, Lightfoot M, Alsyouf M, Nicolay LI, Jellison F, Baldwin DD. A Prospective Randomized Controlled Trial Assessing Diazepam to Reduce Perception and Recall of Pain During Transrectal Ultrasound Guided Biopsy of the Prostate. J
Endourol. 2014 Jul;28(7):881-6. 3
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Kilciler M1, Demir E, Bedir S, Erten K, Kilic C, Peker AF. Pain scores and early complications of transrectal ultrasonography-guided prostate biopsy: effect of patient position. Urol Int. 2007;79(4):361-3. 4
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Otunctemur A1, Dursun M, Besiroglu H, Can Polat E, Cakir SS, Ozbek E, Karadeniz T. The effectivity of periprostatic nerve blockade for the pain control during transrectal ultrasound guided prostate biopsy. Arch Ital Urol Androl. 2013 Jun 24;85(2):69-72. doi: 10.4081/aiua.2013.2.69.
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Anup K1, Pawan V, Niraj K, Biswajit N, Nayan MK. A prospective randomized trial comparing three different analgesic techniques for pain control during transrectal ultrasound guided prostate biopsy: a single center experience. Minerva Urol Nefrol. 2013 Mar;65(1):77-82.
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Jindal T, Mandal SN, Biswas G, Karmakar D.Evaluation of the efficacy of a combination of diltiazem and periprostatic nerve block in pain control during transrectal ultrasonography-guided biopsy of the prostate. Ann R Coll Surg Engl. 2013 Jul;95(5):361-4.
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Kumar A1, Griwan MS, Singh SK, Sen J, Pawar DS. Is periprostatic nerve block a gold standard in case of transrectal ultrasound-guided prostate biopsy? Urol Ann. 2013 Jul;5(3):152-6. doi: 10.4103/0974-7796.115732.
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Eichler K, Hempel S, Wilby J, et al. Diagnostic value of systematic biopsy methods in the investigation of prostate cancer: a systematic review. J Urol 2006 May;175(5):1605-12. Irer B, Gulcu A, Aslan G, Goktay Y, Celebi I. Diclofenac suppository administration in conjunction with lidocaine gel during transrectal ultrasound-guided prostate biopsy: prospective, randomized, placebo-controlled study. Urology. 2005 Oct;66(4):799-802.
10
Ragavan N, Philip J, Balasubramanian SP, Desouza J, Marr C, Javle P. A randomized, controlled trial comparing lidocaine periprostatic nerve block, diclofenac suppository and both for transrectal ultrasound guided biopsy of prostate. J Urol. 2005 Aug;174(2):510-3; discussion 513.
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11
Adsan O, Inal G, Ozdoğan L, Kaygisiz O, Uğurlu O, Cetinkaya M. Unilateral pudendal nerve blockade for relief of all pain during transrectal ultrasound-guided biopsy of the prostate: a randomized, double-blind, placebo-controlled study. Urology. 2004 Sep;64(3):528-31. 12
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Cantiello F, Cicione A, Autorino R, Cosentino C, Amato F, Damiano R. Pelvic plexus block is more effective than periprostatic nerve block for pain control during office transrectal ultrasound guided prostate biopsy: a single center, prospective, randomized, double arm study. J Urol. 2012 Aug;188(2):417-21.
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Haq A, Patel HR, Habib MR, Donaldson PJ, Parry JR. Diclofenac suppository analgesia for transrectal ultrasound guided biopsies of the prostate: a double-blind, randomized controlled trial. J Urol. 2004 Apr;171(4):1489-91.
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ACCEPTED MANUSCRIPT COMPARISON OF BASELINE VARIABLES Group A Group B (n=50) (n=50)
Comorbid Yes No
32 (64%) 18 (36%)
Diabetes Yes No
14 (28%) 36 (72%)
Hypertension Yes No Ischemic heart disease Yes No
34 (68%) 16 (32%)
0.2352
0.4173
15 (30%) 35 (70%)
0.5003
24 (48%) 26 (52%)
26 (52%) 24 (48%)
0.4213
8 (16%) 42 (84%)
9 (18%) 41 (82%)
0.5003
46 (92%) 4 (8%)
0.3453
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43 (86%) 7 (14%)
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Biopsy Sextant Extended
67.3±8.08
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69.1±10.01
p-value
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Age in years1
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Table 1 Variables
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1 Mean±Standard deviation, 2 Student’s t-test, 3 Chi square tests
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COMPARISONS OF PAIN SCORE BETWEEN THE GROUPS Pain score (mean SD)
Time
p-value
Immediately after taking biopsy cores
1.46±1.146
2 hours after biopsy
0.14±0.450
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0.34±0.626
0.032
4.68±0.767
0.000
2.40±0.808
0.000
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0.08±0.274
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At the time of probe insertion
Group B
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Group A
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Enrollment
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Assessed for eligibility (n=113)
Excluded (n= 13) ♦ painful anorectal condition (n= 6 ) ♦ prostatitis (n=4 ) ♦ allergy to diclofenac (n= 3)
Randomized (n= 100)
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Allocation Allocated to lidocaine suppository alone (n=50)
Follow-Up
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Allocated to Diclofenac suppository and lidocaine jel group (n=50)
Lost to follow-up (n=0 )
Lost to follow-up (n= 0) Discontinued intervention (give reasons) (n= )
Analysis Analysed (n= 50)
Analysed (n= 50)
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Treatment arms
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…………Lidocaine jelly only group
_____ Lidocaine jelly + Diclofenac suppository