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Research Article

Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial

[version 1; peer review: 3 approved]
PUBLISHED 08 Dec 2016
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Abstract

TRIAL DESIGN: To compare the difference in pain score during flexible cystoscopy between patients undergoing the procedure with plain lubricating gel  only and plain gel with diclofenac suppository in a randomized control trial.
METHODS:  A total of 60 male patients with an indication of flexible cystoscopy were enrolled in a prospective, randomized controlled study. Patients were randomized in two groups. In group “A”, patients received diclofenac suppository one hour prior to the procedure while group “B” did not receive diclofenac suppository. Both groups received 10 ml of intra-urethral  plain gel for lubrication during flexible cystoscopy. Pain score was recorded immediately after the procedure using the visual analogue scale (VAS). Pre- and post-procedure pulse rate and systolic blood pressure was also recorded. Statistical analyses were performed using chi-square test and student t-test. Regression analysis was performed to address the confounding variables.
RESULTS: Both groups were comparable for variables including age, duration of procedure, level of operating surgeon and indication of procedure. Most common indication for flexible cystoscopy was removal of double J stent. There was a statistically significant difference in the mean pain score between two groups (p = 0.012).  The difference in post-procedure mean pulse rate in the two groups was statistically significant (p= 0.01) however there was no difference observed in mean post procedure systolic blood pressure. Regression analysis showed that none of the confounding variables were significantly affecting pain perception.
CONCLUSIONS: Intra rectal diclofenac suppository is simple and effective pre-emptive analgesia. We recommend its routine use during flexible cystoscopy for better pain control.

Keywords

diclofenac suppository, pain control, flexicystoscopy, office urology

Introduction

The earliest reported use of flexible endoscope for examination of bladder neck was by Tsuchida and Sugawara1. It is now one of the most commonly performed diagnostic as well as therapeutic urologic interventions2. Pain associated with cystoscopy varies from patient to patient and there is continuous effort using various methods to reduce pain during and after the procedure to improve patient compliance for flexible cystoscopy. The majority of patients require local anesthesia or lubricant solution only but some patients may require intravenous sedation3 or inhalation analgesia (nitrous oxide)4. Factors contributing to severity of pain include: lubrication, use of topical anesthesia and duration of cystoscopy57 but the available evidence for best practice in terms of treatment is continuously evolving8. The important issues regarding the correct use of intra-urethral gels are, for the most part, left to individual preference9. Effect of different intra-urethral gels, their dosage, temperature and time of instillation on pain perception has been evaluated in literature. In a randomized control trail, 2% lidocaine gel in two different doses (10 and 20 ml) and plain lubricating gels were found to be equally effective for pain control during flexible cystoscopy (p=0.406)10. Pain perception with use of lidocaine versus plain lubricating gel is less as reported in a meta-analysis by Aaronson et al.11 while another meta-analysis by Patel et al. has reported no statistical difference among the two gels for pain control12. In a study by Komiya et al., oral zaltoprofen has been used as pre-emptive analgesia for rigid cystoscopy and it has been proved to provide better pain control than 2% lidocaine gel alone (11.35 versus 13.69 with a difference of pain score -2.8, p-value 0.0087)13. Intra-rectal diclofenac suppository administration used by Irer et al. has a proven role to reduce pain and improve patients’ tolerance of trans rectal ultrasound-guided prostate biopsy14.

Diclofenac is an anti-inflammatory drug with local and systemic effects; the local effects include reducing the impact of pain mediators. The diclofenac suppository in comparison to the oral has a rapid onset and a slower rate of absorption. The maximal plasma level Is reached within 2 hours, and is maintained for up to 12 hours and that forms the basis of using suppository rather than oral NSAID in our study15. In the current study we have attempted to assess the use of diclofenac suppository as a pre-emptive analgesia during flexible ureteroscopy.

Methodology

Study protocol, patient recruitment and randomization

The Ethical Review Committee of the Aga Khan University and the Clinical Trial Unit approved the study protocol. The study was registered at www.clinicaltrials.gov (ClinicalTrials.gov identifier: NCT01812928). This trial was conducted at the surgical day care unit from February 2013 to July 2013.

Details of recruitment and flow of study has been demonstrated as CONSORT flow diagram. (Figure 1). The principal investigator of this study obtained the written consent from all the qualified patients before randomization. All male patients of 18 years of age and older with indication for flexible cystoscopy, were assessed for recruitment in the trial. We included all adult males who attended for evaluation of hematuria or lower urinary tract symptoms and those for removal of double J ureteral stent. All patients undergoing the procedure had a urinalysis and culture to exclude UTI. Patients were requested to empty the bladder immediately prior to the procedure or within 30 minutes. Prior to the procedure, patients were explained the visual analog scale (VAS; score zero means no pain and 10 means worst pain). Eligible patients were randomized by a computer-generated list and sealed envelopes. Patients were randomized into either Group A (those patients who received diclofenac suppository prior to procedure) or Group B (those patients who did not receive diclofenac suppository prior to procedure) using a web-based random number generator (RANDOM.ORG, Dublin, Ireland; https://www.random.org). Diclofenac suppository (100 mg) was administered rectally 1 hour prior to the procedure in the pre-operative area. Both groups received 10 ml of plain lubricating gel immediately before the procedure for the purpose of lubrication.

d0bb6446-3c70-4235-ab74-a05bf6641036_figure1.gif

Figure 1. CONSORT statement describing the details eligibility, allocation, follow up and analysis of the patients.

d0bb6446-3c70-4235-ab74-a05bf6641036_figure2.gif

Figure 2. Numeric pain rating on a scale of 1–10.

The procedure was performed at the surgical day care unit in supine position by a consultant urologist or senior urology resident (residency year 5 and 6) that was blinded to the randomization group. A second resident immediately following the procedure, collected data (pain score) in the operating room. The VAS consists of a straight line with the endpoints defining extreme limits such as ‘no pain at all’ and ‘pain as bad as it could be’16. The investigator was blinded to the group (independent assessor). Operative time was recorded from the operating room time log. Pre- and post-procedure pulse rate and blood pressure were recorded for all participants.

Data analysis

Data was analyzed using SPSS™ version 17.0. Results were described in terms of mean and standard deviation for age, duration of procedure and pain score while frequency and percentage were mentioned for categorical variables. The student t-test (independent samples, one-tailed) was used to determine statistical significance of VAS for pain between group A and B. Confounder and effect modifiers i.e. age, level of the person performing procedure, indication for procedure and duration of procedure were analyzed using linear regression analysis. p-value of <0.05 was considered as statistically significant.

Results

AgeGroupIndicationDurationPulse pre procedurePulse post procedureSys BP pre procedureSys BP Post procedurePerformed byPain ScoreAdd analgesia
55A126867145140RESIDENT0No
38A167270139140RESIDENT3No
80A1106665128130RESIDENT2No
27A348280140138RESIDENT4No
35A367270135138RESIDENT4No
44A377776116120RESIDENT2No
50A32.56970118120RESIDENT4No
52A336868120115RESIDENT2No
21A367069117119RESIDENT3No
70A376365138130RESIDENT3No
29A39.38884139135RESIDENT6No
22A33.57775125120RESIDENT4No
78A34.26868130135RESIDENT3No
69A377470119120RESIDENT0No
44A388480120120RESIDENT3No
57A388079120115RESIDENT4No
42A387978125130RESIDENT5No
50A356868110110RESIDENT3No
22A33.38179116115RESIDENT4No
52A337980134130CONSULTANT2No
45A367778116115RESIDENT4No
62A228480145140RESIDENT2No
55A236965144148CONSULTANT3No
32A266469114120RESIDENT3No
49A268078120128RESIDENT3No
66A266165119120RESIDENT6No
49A32.37071110115RESIDENT3No
44A396564123120RESIDENT3No
27A33.37875116118RESIDENT3No
54A366668138136RESIDENT4No
65B35.57779116115RESIDENT5No
18B14.86869134140RESIDENT4No
43B197470116148RESIDENT3No
67B17.48490145120RESIDENT3No
53B35.38081144128RESIDENT4No
21B337977114120RESIDENT3No
32B3106870120115RESIDENT4No
57B358180119120RESIDENT6No
19B357981110118RESIDENT5No
28B347777123136CONSULTANT4No
67B3108480116135CONSULTANT3No
26B35.36975138120RESIDENT4No
67B386468117135RESIDENT6No
54B358082138120RESIDENT4No
34B356165139120RESIDENT4No
61B257070125115RESIDENT1No
59B256566130130RESIDENT6No
31B227880119110RESIDENT3No
46B266680120115RESIDENT7No
55B257778120130RESIDENT5No
33B256982125140RESIDENT2No
59B266870110140RESIDENT3No
52B257071145130RESIDENT4No
37B236370139138RESIDENT5No
69B248890128138RESIDENT2No
61B296870140120RESIDENT6No
29B347279135120RESIDENT4No
33B366672116115RESIDENT4No
47B348285118119RESIDENT3No
62B377278120130RESIDENT6No
Group A: Diclofenac + Gel
Group B: Gel alone
Dataset 1.Raw data for ‘Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial’, 2016.
Group A: Diclofenac + Gel; Group B: Gel alone; Indication: 1= LUTS, 2= Haematuria, 3= JJ Stent removal.

Seventy-three patients were evaluated for inclusion in the study. A total of sixty patients were recruited in the trial and analyzed. The mean age was 46.75 ± 16.12 years (IQR: 18–80). The most common indication for flexible cystoscopy was removal of double J Stent (n= 38, 63.3%), others were for evaluation of hematuria (16, 26.7%) and lower urinary tract symptoms (6, 10%). Year 5 and 6 urology residents performed the majority of the procedures (n= 56). Mean duration of the procedure was 5.52 ± 2.13 minutes (IQR: 2–10 minutes). On the 11 point VAS the mean pain score was 3.63 with a standard deviation of 1.46 for the entire group (IQR: 0 – 7). The highest pain score was of 7 on VAS reported by only one patient from group B.

The mean age of the patients in groups A and group B were 48.53 ± 17.81 years and 44.97 ± 14.31 years respectively and there was no statistically significant difference (p= 0.53). The pre-procedure pulse and systolic blood pressures were comparable in both groups. Mean duration of procedure in group A was 5.76 ± 2.25 minutes and in group B was 5.28 ± 2.00 minutes. This difference in duration was not statistically significant (p=0.82). Indications for the procedure and level of operating surgeon were also comparable between the groups.

Mean pain score in group A was 3.16 ± 1.53 and in group B was 4.10 ± 1.24. This difference in the mean pain score was found to be statistically significant (p= 0.012). None of our patients required additional analgesia in either group. The difference in post-procedure pulse rate was found to be statistically significant (p=0.01) between groups however no statistically significant difference (p=0.15) was observed in systolic blood pressure between two groups (Table 1).

Table 1. Basic demographic profile of the patients in the two groups.

ParametersGroup AGroup Bp value
Age (years)
Mean ± SD
48.53 ± 17.844.97 ± 14.30.53
Duration (min)
Mean ± SD
5.76 ± 2,255.28 ± 2.00.82
Indications
JJ stent removal1721
Evaluation of hematuria1060.497
Evaluation of LUTS33
Level of operating surgeon
Consultant urologist22
Senior urology resident28280.694
Post-procedural pulse/min
Mean ± SD
73.5 ± 4.176.4 ± 3.80.01
Post-procedural systolic pressure
Mean ± SD
129.3130.10.15
Pain score on VAS
Mean ± SD
3.16 ± 1.534.10 ± 1,240.012

Linear regression analysis was performed. None of the confounding factors (including age, indication for procedure, level of operating surgeon and duration of procedure) was found to have significant impact on the outcome parameter (r2 = 0.026, standard error of estimate= 1.479; Table 2).

Table 2. Multiple linear regression analysis of factors associated with pain.

Model summary (a) 

ModelRR squareAdjusted
R square
Std error of the
estimate
10.163*0.026-0.0261.47961

* Predictor: (constant), indication for procedure

Duration of procedure (b) 

Coefficients*
ModelUnstandardized
coefficient
Standardized
coefficient
tSig95% CI for B
BStd. ErrorBetaLower
bound
Upper
Bound
1 (constant)4.5481.0554.3012.4346.662
Group-0.2510.387-0.086-0.6470.520-1.0270.526
Duration of
procedure
-0.1010.096-0.147-1.0480.299-0.2930.092
Indication for
procedure
0.0070.2330.0040.0320.975-0.4600.475

Discussion

We examined the effect of pre-emptive analgesia on pain perception during flexible cystoscopy and found out that diclofenac suppository significantly reduces pain when administered as pre-emptive analgesia before flexible cystoscopy.

Randomized studies by Patel et al.12 regarding use of lidocaine versus plain gel, which included 817 patients, showed that intra urethral lidocaine gel had no statistical effect on pain on a 100-point VAS scale (95% CI, -9.6 to 0.385). This meta-analysis challenged the commonly held belief among clinicians that intra urethral lidocaine gel is more efficacious than plain gel for decreasing pain during flexible cystoscopy12. In contrast to the findings of Patel et al.12, Cornel et al. observed slightly less pain (statistically non significant) in the test group and pain perception was the same between patients with past experience of cystoscopy and initial cystoscopy17. To avoid this bias, we kept very strict inclusion criteria and excluded all the patients with previous experience of flexible cystoscopy.

The present study has demonstrated significant reduction in pain perception during flexible cystoscopy in male patients with use of diclofenac suppository as pre-emptive analgesia. Sample size was calculated a priori to detect the effect, according to Lwanga et al.18 We followed stringent criteria for enrollment of patients in this trial to eliminate confounding factors for pain. Computer generated sequences were used for randomization in order to give equal chance of being selected in either group to all recruited patients.

Flexible cystoscopy is often performed repeatedly in particular during the follow up of urothelial cancer. As repeated cystoscopy did not increase the patient's tolerability to pain associated with cystoscopy, Muezzinoglu noted the need for more effective anesthesia to improve tolerability during the procedure and maintain quality of life of the patients under long-term follow-up with repeated cystoscopies19. Till date various techniques have been used to ameliorate the perception of pain during flexible cystoscopy. Use of NSAID as pre-emptive analgesia has been tested for various surgical procedures20,21. Komiya and co-workers examined the effect of anti-inflammatory drug (NSAID) zaltoprofen that inhibits the generation of prostaglandins as well as the pain induced by bradykinin during rigid cystoscopy13. The mean age of the patients in their study was 69.3+/- 8.2 (range: 41–83) while in our study we had relatively younger study subjects (mean age+/- SD, range: 46.75+/-16.1 years, 18–80 years) who are presumably more anxious with lower pain threshold. Despite this fact, diclofenac suppository significantly improved the pain perception and proved to be effective regardless of age on regression analysis. Another matter of debate is the statistical method used in the study by Komiya et al.13 where they used a “one sample Wilcoxon test” for comparing the two groups which is rather an inappropriate test to demonstrate the effect. The one-Sample Wilcoxon signed-rank test is a non-parametric alternative to a one-sample t-test. The test determines whether the median of the sample is equal to some specified value. Data should be distributed symmetrically about the median. In the present study we have used regression analysis, which is a more stringent method to demonstrate the effect.

In our study, we used diclofenac suppository as pre-emptive analgesia. The pharmacokinetics of the suppository form is quite different from the orally administered agent. It acts as an anti-inflammatory drug both locally and systemically, by minimizing the effects of local mediators involved in the pain response. Diclofenac has been marketed internationally since 1973 and is currently available in oral, rectal, parenteral and topical preparations15. The efficacy of the diclofenac suppository is due to more rapid onset of effect, and a slower rate of absorption (it takes approximately 4.5 hours for complete absorption) than oral enteric-coated tablets. The maximal plasma level is attained within 2 hours, and it is maintained for up to 12 hours15. The terminal half-life of diclofenac in plasma is 1 to 2 hours. The major route of excretion is the urine (~60%) and a small percentage through bile in the feces22. Its role has proven to be effective for pain control during trans rectal ultra sound guided prostate biopsy in study by Haq et al.23. In a case control the investigators noted that it is a simple and safe method. While Irer et al.14 showed additional benefit of using lidocaine gel for pain control during the same procedure but statistical significance of this study is in question due to its smaller sample size.

In the present study, appropriate sample size, stringent criteria for recruitment, computer generated randomization, proper statistical methods and analysis has increased the scientific rigor. This was not a placebo controlled as various per rectally medications or “dummy drugs” may have some local inflammatory effect.

Conclusion

Intra rectal diclofenac suppository is a simple and effective method to reduce pain during flexible cystoscopy regardless of age. We recommend its routine use for better tolerability of pain and to increase patient’s compliance.

Data availability

F1000Research: Dataset 1. Raw data for ‘Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial’, 2016, 10.5256/f1000research.9519.d14526824

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Nadeem M and Ather MH. Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial [version 1; peer review: 3 approved]. F1000Research 2016, 5:2834 (https://doi.org/10.12688/f1000research.9519.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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ApprovedThe paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approvedFundamental flaws in the paper seriously undermine the findings and conclusions
Version 1
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PUBLISHED 08 Dec 2016
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Reviewer Report 27 Feb 2017
Christian Bach, Department of Urology, RWTH Aachen University Hospital, Aachen, Germany 
Approved
VIEWS 3
The authors need to be congratulated for this randomised controlled trial comparing pain during flexible cystoscope with or without rectal diclofenac. The methodology is sound and the paper is conclusively written. The discussion is covering the relevant literature and the ... Continue reading
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Bach C. Reviewer Report For: Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial [version 1; peer review: 3 approved]. F1000Research 2016, 5:2834 (https://doi.org/10.5256/f1000research.10254.r20039)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Reviewer Report 17 Feb 2017
Michael Chrisofos, 2nd Department of Urology, Sismanoglio General Hospital, National and Kapodistrian University of Athens, Athens, Greece 
Approved
VIEWS 4
Usage of diclofenac suppository, seems to be an excellent choice, based on the results of this revelatory research, so I congratulate the authors for running a well-designed trial and obtained an acceptable scientific standard.
 
The issue ... Continue reading
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HOW TO CITE THIS REPORT
Chrisofos M. Reviewer Report For: Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial [version 1; peer review: 3 approved]. F1000Research 2016, 5:2834 (https://doi.org/10.5256/f1000research.10254.r20345)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 20 Feb 2017
    M Hammad Ather, Aga Khan University, Karachi, Pakistan
    20 Feb 2017
    Author Response
    We appreciate the comments and input by Dr Chrisofos. He raised an important point concerning difference in pain perception related to gender and age. The current study was conducted only ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 20 Feb 2017
    M Hammad Ather, Aga Khan University, Karachi, Pakistan
    20 Feb 2017
    Author Response
    We appreciate the comments and input by Dr Chrisofos. He raised an important point concerning difference in pain perception related to gender and age. The current study was conducted only ... Continue reading
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Reviewer Report 19 Dec 2016
Noor Buchholz, U-merge (Urology in Emerging Countries), London, UK 
Krishanu Das, Royal Adelaide Hospital, Adelaide, SA, Australia 
Approved
VIEWS 16
K Das and N Buchholz: Comment on “Nadeem M and Ather MH. Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial [version 1; referees: awaiting peer review]. F1000Research 2016, 5:2834 (doi: 10.12688/f1000research.9519.1)”

Firstly, ... Continue reading
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HOW TO CITE THIS REPORT
Buchholz N and Das K. Reviewer Report For: Effect of diclofenac suppository on pain control during flexible cystoscopy-A randomized controlled trial [version 1; peer review: 3 approved]. F1000Research 2016, 5:2834 (https://doi.org/10.5256/f1000research.10254.r18368)
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
  • Author Response 29 Dec 2016
    M Hammad Ather, Aga Khan University, Karachi, Pakistan
    29 Dec 2016
    Author Response
    We thank Drs. Buccholz and Das for their valuable comments on the above submission. In response to the questions raised:
    1. No we did not find any difference in
    ... Continue reading
COMMENTS ON THIS REPORT
  • Author Response 29 Dec 2016
    M Hammad Ather, Aga Khan University, Karachi, Pakistan
    29 Dec 2016
    Author Response
    We thank Drs. Buccholz and Das for their valuable comments on the above submission. In response to the questions raised:
    1. No we did not find any difference in
    ... Continue reading

Comments on this article Comments (0)

Version 1
VERSION 1 PUBLISHED 08 Dec 2016
Comment
Alongside their report, reviewers assign a status to the article:
Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested
Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.
Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions
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