UNCLASSIFIED Tamsulosin and Sodium Diclofenac as an Effective Therapy to Reduce Pain After Ureteral Stent Removal: A Prospective, Double Blinded Randomized Placebo Controlled Trial Exsa Hadibrata1, Ahmad Farishal2, Zulfikar Ali3, R Danarto4 Purpose: This study was conducted to determine the effects of tamsulosin and diclofenac sodium use on patients' pain perception after ureteral stents removal. Materials and Methods: This study was a randomized control trial with double-blinded design. Eighty patients who underwent ureteral stent removal surgery at Kardinah Hospital during January to March 2017 were divided into four groups. The following medications were administered for two days, (A) placebo tid, or (B) diclofenac sodium 50 mg bid, or (C) tamsulosin 0.2 mg sid, or (D) combination of tamsulosin and diclofenac sodium. Analge- sic effects were assessed with the Visual Analog Scale (VAS). Relationships among variables were assessed using one-way ANOVA and post hoc tests. Results: The surgical procedure for ureteral stent removal consisted of 48 (60%) male and 32 (40%) female. The average age of group A, B, C, and D were 51.0, 51.9, 47.6, and 47.3 years, and the average stent dwell time was 6.3 weeks. VAS values of the entire experimental group were lower than the control group on the first day until the second day after the stent removal (p < 0.05). In the experimental group, there was no difference between group B and C (p > 0.05). Group D showed better analgesic effects than group B and C (p <0.05). No severe side effects were observed. Conclusion: The result shows that combination therapy of diclofenac sodium and tamsulosin is better in reducing the pain after ureteral stent removal compared to the admission of a single placebo, tamsulosin, or diclofenac so- dium therapy. Keywords: tamsulosin; diclofenac sodium; pain; stent removal INTRODUCTION Ureteral stents are now commonly used by urolo-gists, but the usage of ureteral stents often causes significant morbidity for patients. Some patients ex- perience pain and urinary disorders during stent use.(1) Several studies have been conducted to determine the complications after stent removal. As many as 64% of patients undergoing stent removal reported complaints, including pain, hematuria, frequency, urgency, or fever, with pain as the most common one.(2) Thirty-two per- cent of patients reported delayed severe pain after they had their ureteral stent removed, and 9% visited the in- tensive care unit.(3) Pain management in transurethral postoperative pa- tients is an issue of concern. In general, postoperative regional and local anesthesia have both the advantages and disadvantages for patient morbidity.(4) Therefore, those type of anesthesia is replaced by oral and topical analgesics such as opioids, sedatives and non-steroidal anti-inflammatory drugs (NSAIDs) for irritation and pain management of postoperative urological endosco- py.(5) Non-steroidal anti-inflammatory drugs (NSAIDs) 1Department of Urology, Faculty of Medicine Universitas Lampung/ Abdul Moeloek General Hospital, Lampung, Indonesia. 2Medical Doctor Departmet Of Urology, Faculty Of Medicine Universitas Lampung, Lampung, Indonesia. 3Department of Surgery, Kardinah Hospital, Tegal, Central Java, Indonesia. Yogyakarta, Indonesia. 4Department of Surgery, Faculty of Medicine Universitas Gadjah Mada/Dr Sardjito General Hospital. *Correspondence: Department of Urology, Faculty of Medicine Universitas Lampung/ Abdul Moeloek General Hospital, Lampung, Indonesia. E mail: exsa.hadibrata@gmail.com. Received February 2019 & Accepted December 2019 are commonly used drugs that have antipyretic and an- algesic effects. This drug works in alleviating the post- operative pain by preventing the production and release of prostaglandins.(6) Diclofenac sodium is one of the recommended types of NSAIDs for postoperative uro- logical endoscopy patients.(7) Research on pain percep- tion after stent removal is very limited in number. In a previous study, it was mentioned that the administration of a single dose of the non-steroidal anti-inflammatory drug (NSAID) prevented severe pain after the remov- al of a ureteral stent.(8) Other studies stated that the combination of silodosin and diclofenac sodium was effective in reducing pain after ureteral stent removal. (9) The combination of tamsulosin and propiverine also decreased irritative voiding symptoms, suprapubic pain and improved the quality of life of the patients with DJ stent.(10-11) Tamsulosin is an α1 selective blocker drug. Alpha 1 receptors distributed in the prostate, bladder, and ureter. The use of tamsulosin can cause a decrease in ureteral contractions, as well as reduce irritation in the trigone area. This is a mechanism for reducing pain in pain caused by ureteric stents in the use of tamsu- Urology Journal/Vol 18 No. 1/ January-February 2021/ pp. 111-116. [DOI: 10.22037/uj.v0i0.5190] losin.(12-14) The study examined the patient's complaints, and Visual analog score (VAS) score after removal of DJ stents. This study was conducted to determine the effect of tamsulosin and diclofenac sodium use on pain per- ception of patients after ureteral stent removal METHODS Study Design This study was a prospective, randomized, double-blind, placebo-controlled trial. The number of samples is de- termined based on comparative numerical analysis. The study compared the analgesic effects following endo- scopic removal ureteral stent surgery. Pain perception was assessed from the first day until the second day fol- lowing surgery. Analgesic drugs were administered for two days following surgery. The analgesic effects were assessed using the Visual Analog Scale (VAS). All pa- tients above 17 years and below 55 years undergoing unilateral ureteral stenting following renal and ureteric stone surgery were included. No history was presented of psychotic mental illness, organic psychiatric condi- tions, and other mental illnesses, severe pain-induced illnesses and malignancy. Patients with open surgery conversion, history of peptic ulcer disease, liver im- pairment, chronic renal failure, coronary artery disease, bleeding diathesis, asthma, urinary tract infections (UTI), chronic painful conditions like arthritis, preg- nancy, allergy to medications, significant lower urinary tract symptoms (LUTS) and use of alpha-blockers and residual calculus were excluded. Patients with compli- cations during stent removal like hematuria and mu- cosal injury were also excluded. The study was initiated after obtaining the approval of the Institutional Ethics Committee at Kardinah Hospital. Ref: 071/001/2017. Interventions The patients who underwent endoscopic surgery re- moval ureteral stent at Urology health center Kardi- nah Hospital, Tegal from January 2017 to April 2017 Unclassified 112 Table 1. Patient characteristic Variable Overall (A) Placebo (B) Diclofenac (C) Tamsulosin (D) Combination Age (year), Mean (SD) 49.6 (11.7) 51.0 (13.1) 51.9 (10.6) 47.6 (11.4) 47.3 (11.8) Stent insitu duration (week), Mean (SD) 6.3 (2.8) 6.0 (2.4) 66 (30) 5.5 (2.5) 6.9 (3.1) Gender, n (%) • Male 48 (60) 9 (45) 11 (55) 13 (65) 13 (65) • Female 32 (40) 11 (55) 9 (45) 7 (35) 7 (35) Stent location, n (%) • Right 44 (55) 14 (70) 10 (50) 11 (55) 9 (45) • Left 36 (45%) 6 (30) 10 (50) 9 (45) 11 (55) Diagnose, n (%) • Renal stone 26 (32,5) 6 (30) 6 (30) 8 (40) 8 (40) • Ureteral stone 54 (67,5) 14 (70) 14 (70) 12 (60) 12 (60) Previous operation, n (%) • Endourology 43 (53,8) 11 (55) 9 (45) 10 (50) 10 (50) • Open surgery 37 (46,3) 9 (45) 11 (55) 10 (50) 10 (50) VAS score after removal stent, n (%) • < 3 39 (48,7) 1 (5) 13 (65) 9 (45) 16 (80) • 3-5 38 (47,5) 18 (90) 7 (35) 9 (45) 4 (20) • >5 3 (3,7) 1 (5) 0(0) 2 (10) 0 (0) Complication • Colic Pain 3 (3,7) 2 (10) 1 (5) 0 (0) 0 (0) • Hematuria 4 (5) 2 (10) 1 (5) 1 (5) 0 (0) • Frequency and urgency 4 (5) 4 (20) 0 (0) 0 (0) 0 (0) • No complication 69 (86,2) 12 (60) 18 (90) 19 (95) 20 (100) Figure 1. Flowchart of randomized control trial study design Tamsulosin & Diclofenac in reducing stent pain-Hadibrata et al. were included. The experimental groups (B, C, and D) consisted of 20 patients in each group, and the control group also (A) consisted of 20 patients. In control group A, patients were administered vitamin tablet containing folic acid tid for two days. In group B, patients were administered diclofenac sodium 50 mg twice a day for two days. In group C, 0.2 mg of tamsu- losin was applied once a day for two days. Group D was administered combination diclofenac 50 mg twice a day and tamsulosin 0,2 mg once a day for two days. All medications were placed in a numbered envelope as per the computer-generated model. All patients received a single dose of levofloxacin 500 mg before stent re- moval as per our department protocol. All patients and investigators were blinded to the medicine identity and randomization design until the end of the study. Visual analog score (VAS) was taken on a scale from zero to ten, zero meaning no pain to 10, meaning excruciating pain. The surgeon removing the stent was also blinded about the grouping. Stent removal was performed under local anesthesia using 2 % xylocaine jelly under vision with 15 Fr cystoscope. The stent used in this study was a double j stent with a diameter of 5 Fr and a length of 26 cm. All patients were contacted after 24 h and 48 h. VAS score, additional medications requirement, and site of pain, and any other relevant parameters were recorded. Statistical Analysis Age, gender, week of ureteral stenting, stent location (right or left), diagnosis, previous surgery, patient sat- isfaction, adverse events, patient complaints, and VAS scale for each patient were recorded. Statistical analy- sis of data that is normal and homogeneously distrib- uted then followed by a one way ANOVA parametric test. However, if it does not meet the requirements for a parametric test, then a non-parametric test, namely Kruskal-Wallis, followed by the Mann Whitney post- hoc analysis to see the differences between treatment groups was employed. A p-value of less than 0.05 was considered to be statistically significant RESULTS In this research, 80 patients who met the inclusion cri- teria were divided into four study groups. The average age of the entire sample was 49.6 years involving 48 male patients and 32 female patients. Primary data analysis included the length of stents dwell times, stent placement, diagnosis, types of operation, VAS score < 3, 3-5, >5 and complication after up DJ stent were re- corded the entire groups. Characteristics of the patients are tabulated in Table 1. In the four groups, the VAS score was analyzed after stent removal. The assessment was performed at 24 hours and 48 hours post-operation. At 24 hours af- ter stent removal, the mean VAS scores in the place- bo group were 4.0; diclofenac sodium group was 2.4, tamsulosin group was 2.6, and the combination group was 1.8. Furthermore, at 48 hours after stent removal measurement, the mean VAS score in the placebo group was 2.5, the diclofenac sodium group was 1.0, the tam- sulosin group was 1.1, and combination group was 0.5 (Table 2). In the post hoc analysis, there was a signif- icant difference in the VAS score of the combination therapy group compared to the entire group (Table 3; p < 0.05). DISCUSSION Pain management is currently a significant issue among urologists. Unrelieved pain can be a major medical Tamsulosin & Diclofenac in reducing stent pain-Hadibrata et al. Table 2. VAS Mean Score Before-After removal stent Condition Placebo Na Diclofenac Tamsulosin Combination Pre-Op 0,9 0,7 0,95 1,1 Post Op Day 1 4 2,45 2,65 1,85 Post Op Day 2 2,4 1 1,15 0,55 Figure 2. Pain scale graphic Vol 18 No 1 January-February 2021 113 Unclassified 114 problem. In the late 1990s, pain management in the transurethral surgical procedures was established. (6,11) However, many urologists did not understand yet how to address the post-operative acute pain problems in patients undergoing endoscopic surgery. The primary goal of endoscopic post-operative pain management is to overcome the pain with minimal side effects of drugs.(11,15) The use of a ureteral stent is significantly associated with the pain and discomfort experienced by the pa- tient.(1) In patients with a history of Double-J insertion, the perception of Catheter-Related Bladder Discomfort (CRBD) is less in comparison with patients without such a history.(22) As many as 80% of patients reported experiencing pain due to stent.(1) In another study, 64% of patients who underwent ureteral stent removal reported complaints, including pain, hematuria, frequency, urgency or fever, and the major complaint was pain.(2) Several studies have been conducted to reduce the pain and discom- fort caused by ureteral stent use by using alpha-block- er, anti-cholinergic, and phosphodiesterase inhibitor as well as the design, material and dimension of the stent. (10,16-19) Almost all the existing literature focus on the morbidity of the ureteral stent when the stent is in situ. Frequently, the urologists have patients with colic-like pain after ureteral stent removal, requiring addition- al analgesic and hospitalization for severe pain cases. Previous studies reported that as many as 32% of pa- tients complained about the delayed severe pain after ureteral stent removal, and 9% returned to the intensive care unit to be treated.(3) In this study, pain assessment was performed using VAS score at 24 hours and 48 hours after ureteral stent removal. The administration of diclofenac sodium, tamsulosin, and the combination of both significantly reduced pain after stent removal compared to placebo (p < 0.001). This result lasted up to 24 hours and 48 hours after the operation. Pain during ureteral stent removal is due to the activa- tion of the nociceptor. Friction between the stent and ureteral mucosa irritates the ureteric smooth muscle, trigonal irritation, and induces pressure changes in the pelvicocalices system.(9) Tamsulosin is a selective α1 blocker drug. Alpha 1 receptors are distributed in the prostate, vesica urinaria, and ureter. The use of tamsu- losin may cause a decrease in ureteral contraction as well as reducing irritation in the trigonum area. It is a pain-reducing mechanism for the pain caused by ure- teral stent.(18-20) Diclofenac sodium is one recommended type of NSAIDs for post-operative urological endos- copy patients, and it is a standard drug in renal colic. (7) COX inhibitors and Non-selective COX inhibitors, significantly reduce ureteral contraction in the human and porcine ureter.(20) In addition, the use of diclofenac sodium drugs can reduce renal blood flow resulting in analgesic and anti-inflammatory effects.(21) There was no significant difference in VAS score be- tween the diclofenac sodium group and the tamsulosin group (p > 0.05). In the diclofenac group, the mean VAS score was lower than that of tamsulosin. At 24 hours post-operative, VAS score of the diclofenac sodi- um group was 2.4 and 2.6 in the tamsulosin group. At 48 hours post-operative, VAS score of the diclofenac sodium group was 1.0 and 1.1 in the tamsulosin group. These results were consistent with the previous stud- ies which stated that there was no significant difference in VAS score in the diclofenac sodium group and al- pha-blocker silodosin.9 The incidence of pain with VAS score of ≥ 3- ≤ 5 was the most prevalent in the placebo group (90%). In the diclofenac sodium group and tamsulosin group, the score was 35% and 55% respectively. While in the combination group, the in- cidence of pain with a VAS score of ≥ 3- ≤ 5 was 20%, and VAS score > 5 was 0%. These results suggest that the occurrence of severe pain can be prevented by providing a combination of diclofenac sodium and tam- sulosin. In this study, the admission of combination therapy was better in reducing the VAS score of 24 hours and Table 3. Post Hoc analysis p value VAS score Day 1 Day 2 Combination Placebo 0.000 0.000 Tamsulosin 0.039 0.039 Diclofenac 0.234 0.020 Tamsulosin Placebo 0.000 0.000 Diclofenac 1.000 0.951 Diclofenac Placebo 0.000 0.000 Characteristic Our study Gangkak et al., 20169 Irfansyah et al., 201610 Tadros et al., 20128 Study design Prospective, double Prospective, double blinded Prospective, single blinded Prospective, double blinded blinded randomized randomized control trial study randomized control trial study randomized control trial study control trial study Regiment Diclofenac sodium Diclofenac sodium and silodosin Tamsulosin and propiverine HCL Rofecoxib and tamsulosin Total sample 80 240 30 22 VAS measure 24 hours dan 48 24 hours post surgery While stent insitu and 24 hours 24 hours post surgery hours post surgery post surgery Conclusiom Combination therapy of Combination therapy of diclofenac Tamsulosin is better compared to Rofecoxib single therapy prior diclofenac sodium and sodium and silodosin did not differ Propiverine HCl in reducing pain, to stent release prevents severe tamsulosin is better in significantly compared to the but Propiverine HCl is better at pain post-release of ureteral reducing the pain after admission of singe silodosin and increasing QoL and decreasing stent ureteral stent removal sodium diclofenac therapy IPSS score compared to the admission of single placebo, tamsulosin, and diclofenac sodium therapy Table 4. Comparison of research results 8,9,10 Tamsulosin & Diclofenac in reducing stent pain-Hadibrata et al. 48 hours postoperatively, compared with other groups (p < 0.05). We did not find any significant side effects on the combination therapy of diclofenac sodium and tamsulosin. The most common side effect of the ad- ministration of diclofenac sodium was gastrointestinal symptoms. In this study, we did not find any significant gastrointestinal complaints and urinary complaints (col- ic pain, hematuria, and frequency-urgency) in the use of drug combinations sodium diclofenac 50 mg twice daily and tamsulosin 0.2 mg once daily for two days. When compared to previous studies, this study did not only evaluate the 24 hours post-operative pain scores, but it continued the evaluation until 48 hours postop- eration.(9) The results of combination therapy remained better in reducing the 48 hours post-operative pain of the VAS score. Results and conclusions in this study, compared with other researches, is presented in Table 4. This study, nevertheless, has some disadvantages. First, in this study, the numbers of randomized samples are few, and the population of this study are limited to a dis- trict hospital in central java only. Future researches are expected to develop the types of therapy and surgery techniques that can significantly reduce the pain after ureteral removal. CONCLUSIONS Our study showed that the combination therapy between diclofenac sodium and tamsulosin is better in reducing pain after ureteral removal than placebo, tamsulosin, and diclofenac sodium admission. CONFLICT OF INTEREST The authors reported no potential conflict of interest. REFERENCES 1. Joshi HB, Stainthorpe A, MacDonagh RP, Keeley FX, Timoney AG, Barry MJ. Indwelling ureteral stents: evaluation of symptoms, quality of life and utility. J Urol 2003; 169:1065-9. 2. Theckumparampil N, Elsamra SE, Carons A, Salami SS, Leavitt D, Kavoussi A, et al. Symptoms after removal of ureteral stents. J Endourol 2015; 29:246-52. 3. Loh-Doyle JC, Low RK, Monga M, Nguyen MM. Patient experiences and preferences with ureteral stent removal. J Endourol 2015; 29:35-40. 4. Tyritzis SI, Stravodimos KG, Vasileiou I, Fotopoulou G, Koritsiadis G, Migdalis V, et al. Spinal versus General Anaesthesia in Postoperative Pain Management during Transurethral Procedures. ISRN Urol 2011; 895874:1-6. 5. Liu J, Zang YJ. Comparative study between three analgesic agents for the pain management during extracorporeal shock wave lithotripsy. Urol J 2013; 10:942-5. 6. Kara C, Resorlu B, Cicekbilek I, Unsal A. Analgesic efficacy and safety of nonsteroidal anti-inflammatory drugs after transurethral resection of prostate. Int Braz J Urol 2010; 36;49-54. 7. Borda AP, Sonnek FC, Fontetne V, Papaioannou EG. Guidelines on Pain Management & Palliative Care. European Association of Urology 2014; 28-33. 8. Tadros NN, Bland L, Legg E, Olyaei A, Conlin MJ. A single dose of a non-steroidal anti- inflammatory drug (NSAID) prevents severe pain after ureteric stent removal: a prospective, randomised, double-blind, placebo-controlled trial. BJU Int 2012; 111:101-5. 9. Gangkak G, Teli RD, Yadav SS, Tomar V, Priyadarshi S, Aggarwal SP. A single oral dose of silodosin an d diclofenac sodium is effective in reducing pain after ureteric stent removal: a prospective, randomized, double blind placebo controlled study. Springerplus 2016; 5:23. 10. Irfansyah. Effect of alpha blocker and anti cholinergic on ureteral stent related symptoms : A single-blind randomized clinical trial. [Tesis]. Universitas Gadjah Mada. 2016. 11. Yuri P, Ali Z, Rasyid N, Birowo P. Effect of ppemidic acid, phenazopyridine HCL, and sodium diclofenac on pain perception following endoscopic urological surgery: Double-blinde randomized-controlled trial. Acta medica indones 2016; 48:184-92. 12. Beddingfield R, Pedro RN, Hinck B, Kreidberg C, Feia K, Monga M. Alfuzosin to relieve ureteral stent discomfort: a prospective, randomized, placebo controlled study. J Urol 2009; 181:170-6. 13. Itoh Y, Kojima Y, Yasui T, Tozawa K, Sasaki S, Kohri K. Examination of alpha 1 adrenoceptor subtypes in the human ureter. Int J Urol 2007; 14:749-53. 14. Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006; 147(Suppl 2):88-119. 15. Yesil S, Polat F, Ozturk U Dede O, Imamoglu M, Bozkirli. Effect of different analgesic on pain relief durung extracorporeal shock wave litotripsi. Hippokratia 2014; 18:107-9. 16. Damiano R, Autorino R, De Sio M, Giacobbe A, Palumbo IM, D'Armiento M. Effect of tamsulosin in preventing ureteral stent-related morbidity: a prospective study. J Endourol 2008; 22:651-6. 17. Deliveliotis C, Chrisofos M, Gougousis E, Papatsoris A, Dellis A, Varkarakis IM. Is there a role for alpha1-blockers in treating double-J stent-related symptoms. Urology 2006; 67:35- 9. 18. Dellis A, Joshi HB, Timoney AG, Keeley FX. Relief of stent related symptoms: review of engineering and pharmacological solutions. J Urol 2010; 184:1267-72. 19. Gupta M, Patel T, Xavier K, Maruffo F, Lehman D, Walsh R, et al. Prospective randomized evaluation of periureteral botulinum toxin type A injection for ureteral stent pain reduction. J Urol 2010; 183:598- 602. 20. Nakada SY, Jerde TJ, Bjorling DE, Saban R. Selective cyclooxygense-2 inhibitors reduce ureteral contraction in vitro: a better alternative for renal colic? J Urol 2000; 163:607-12. Tamsulosin & Diclofenac in reducing stent pain-Hadibrata et al. Vol 18 No 1 January-February 2021 115 21. Chaignat V, Danuser H, Stoffel MH, Z’brun S, Studer UE, Mevissen M. Effects of a non-selective COX inhibitor and selective COX-2 inhibitors on contractility of human and porcine ureters in vitro and in vivo. Br J Pharmacol 2008; 154:1297-307. 22. Maghsoudi R, Niaki SF, Etemadian M, Kashi AH, Shadpour P, Shirani A, et al. Comparing the Efficacy of Tolterodine and Gabapentin Versus Placebo in Catheter Related Bladder Discomfort After Percutaneous Nephrolithotomy: A Randomized Clinical Trial. J Endourology 2018; 32:168-174. Tamsulosin & Diclofenac in reducing stent pain-Hadibrata et al. Unclassified 116