A Randomized Control Trial Comparing Combined Glandular Lidocaine Injection and Intraurethral Lidocaine Gel with Intraurethral Lidocaine Gel Alone in Cystoscopy and Urethral Dilatation Shahram Gooran,1 Pejman Pourfakhr,2 Shirin Bahrami,1 Alimohammad Fakhr Yasseri,1* Amir Javid,1 Negar Behtash,1 Gholamreza Pourmand1 Purpose: Cystoscopy is one of the most common urologic procedures. The aim of this study is to investigate the combined effect of intraurethral lidocaine gel and intraglandular injection of lidocaine 2% on pain during and after cystoscopy. Materials & Methods: In this double-blind, parallel group randomized clinical trial, 156 patients referred for dou- ble J removal, urethral dilatation, or cystoscopy were enrolled. The patients were divided into two groups, A and B. All patients received 20 cc of intraurethral lidocaine gel 2%. In group A (N = 75), lidocaine 2% was also injected into the glans penis. The patients in group B (N = 81) only received the intraurethral lidocaine gel. Cystoscopy was performed 10 minutes later. The primary outcome of interest was measured in terms of pain score (visual analogue scale) during and 5 minutes after cystoscopy. Results: Immediate pain score after the procedure was 3.4 ± 3 and 4.6 ± 3 in groups A and B, respectively (P = .011). Conclusion: Based on the findings of the present study, lidocaine injection into the glans penis significantly re- duced pain perception. Keywords: pain perception; cystoscopy; local anaesthesia. 1Urology Research Center, Sina Hospital, Tehran University of Medical Sciences, Hassan-Abad Sq., Tehran, Iran 2Department of Anesthesiology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran *Correspondence: Sina Hospital, Tehran, Iran. Tel:0098 9122451541. E-mail:yasseri_2006@yahoo.com. Received May 2016 & Accepted May 2017 INTRODUCTION Cystoscopy is one of the most common urologic pro-cedures(1). Cystourethroscopy is a urological proce- dure to view the urethra and bladder(2). When lidocaine is injected into the glans penis, it spreads easily around the urethra and paralyses the sensory nerves around the urethra and anaesthetizes the urethra. Outpatient cystos- copy under intracorporal anaesthesia has several advan- tages over the same procedure under general or spinal anaesthesia in the operating room: The risks of general or spinal anaesthesia, headache, and nausea, are avoid- ed; the urologist can perform this surgical procedure in his office and the total cost is reduced markedly(3). In 2005, Chen and his colleagues performed a rand- omized, double-blind trial in Taiwan on the analgesic effect of lidocaine gel during cystoscopy. They showed that intraurethral lidocaine gel injection is a cost-ef- fective analgesic method, which dramatically reduces the need for analgesic use after cystoscopy(4). Chang et al. performed a study in China in the same year on the effect of intracorpus spongiosum lidocaine injec- tion before certain urological procedures, including the endoscopic removal of stone and internal urethrotomy. They concluded that this anaesthetic could significantly decrease pain in 90% of the patients(3). Several clinical trials have been conducted to find the most suitable way of making this procedure more tol- MISCELLANEOUS erable. Using local anaesthesia before cystoscopy has many benefits over the use of general or spinal anaes- thesia(3-6). Although intracorpus spongiosum lidocaine injection has been used in a few studies around the world for cer- tain endoscopic procedures, it has not been used in cys- toscopy(3). By applying this method of anaesthesia, cys- toscopy can be done in the urologist's office and is less expensive than conducting one in an operating room. This randomized trial compared the combined effect of intracorpus spongiosum lidocaine injection plus intrau- rethral lidocaine gel with the effect of intraurethral gel injection alone on pain perception during cystoscopy and urethral dilatation. MATERIALS AND METHODS Study population Male patients referred for double J stent removal, ure- thral dilatation or cystoscopy between March 2014 and March 2015 entered the study. The exclusion criteria were the presence of meatal ulcers, acute prostatitis, and prolonged cystoscopy for more than 20 minutes. Each patient provided written informed consent and the study was performed in accordance with rules of the 1989 Declaration of Helsinki. The patients’ enrolment algorithm has been illustrated in Figure 1. A course of antibiotics was used before the intervention Vol 14 No 04 July-August 2017 4044 and they were compared by the Kolmogorov-Smirnov test. The values of P < .05 were considered statistically significant. RESULTS In this interventional study, 156 patients undergoing cystoscopy or urethral dilatation were evaluated. Over- all, 75 patients (48.1%) received a combination of li- docaine injection 2% and intraurethral lidocaine gel (group A) and 81 patients (51.9%) received intraure- thral lidocaine gel alone (group B). The procedure type was cystoscopy in 120 (76.9%) and urethral dilatation in 36 (23.1%) patients. The cause of cystoscopy was diagnostic in 45 (28.8%), double J stent removal in 97 (62.2%), double J stent removal of transplanted kidney in 10 (6.4%) and was associated with urethral dilatation in 2 (1.3%) patients. The mean age of the patients was 49.9 ± 17.5 years. The average age was 49.7 ± 17.3 in group A and in 50.3±17.9 in group B (P = .83). The mean cystoscopy duration was 5.4±4.1 minutes. The cystoscopy duration did not differ significantly in the two groups (5.12 ± 4.12 minutes in group A versus 5.6±4.1 minutes in group B, P = .52). The mean pain score (VAS) was 4.1±3.1 and 1.4±1.7 immediately and 5 minutes after the procedure, respectively. The pain scores (number scale) during the procedure were 3.4 ± 3 in group A and 4.6 ± 3 in group B (P = .011). The pain scores (face scale) during the procedure were 2.3 ± 1.7 in group A and 3.1 ± 2.0 in group B (P =. 008). On the other hand, five minutes after the pro- cedure no significant difference was found between the two groups in terms of the pain score. Also, no signifi- cant differences were observed in pre- and post-proce- dural blood pressure and heart rate or in blood pressure between the two methods (Table 1). Then, this comparison was done for cystoscopy and the urethral dilatation procedure separately. The pain scores during the procedure (number scale) were 3.9 ± 3.2 and 4.8 ± 3.1 in groups A and B, respectively (P = .061). Although the pain was more in group B, this in the case of a positive urine culture. In patients with negative urine culture, a single dose of 80 mg genta- mycin was administered intramuscularly, 15 minutes before the procedure. The patients were observed for an hour after the procedure and they were warned about major complications. Study design This study was a double-blind, randomized clinical trial performed in Sina Hospital, Tehran, Iran. One hundred and fifty-six patients were randomly categorized in two groups, A and B. We explained the visual analogue scale (VAS) (a ten numbers scale and 6 faces scale) be- fore the procedure to the patients. The other variables included age, demographic data, blood pressure, and pulse rate before and after the procedure. The patients were divided into groups A (lidocaine 2% injection+in- traurethral lidocaine gel group) and B (intraurethral li- docaine gel alone group). Surgical technique Each cystoscopy was performed with a rigid cystoscope with 22 Fr sheet and 30 degree lens and urethral dila- tation was done with metal dilatators. All procedures were performed by a single urologist. After the patients' preparation and draping, all the patients received 20 cc of intraurethral lidocaine gel 2%. In group A, lidocaine 2% was also injected into the glans penis with a 5 ml syringe and 31 gauge needle. The injection was pushed in 2 or 10 o' clock of glans. The injection site was two millimetres from the meatus and two millimetres from the glans edge. The cystoscopy was performed ten min- utes later. The pain experienced was assessed using the visual analogue scale immediately after the procedure (termed during the procedure for the purpose of this study) and five minutes later. Outcome assessment The primary outcome was the pain score (VAS) dur- ing and after five minutes. The secondary outcomes in- cluded blood pressure and pulse rate changes. After the collection of data, they were analysed with the software SPSS version 21, using descriptive and analytical anal- yses. The qualitative data were presented by mean ± SD Lidocaine injection with gel in cystoscopy-Gooran et al. Figure 1. Patients’ enrollment algorithm Miscellaneous 4045 difference in pain between the two groups was not sta- tistically significant (Table 2). DISCUSSION This study shows that compared to intraurethral lido- caine gel alone, local anaesthesia with direct injection of lidocaine into the glans penis significantly reduces pain perception immediately after cystoscopy or ure- thral dilation (Figure 1). However, no significant dif- ference in pain perception was found between the two groups five minutes after the injection. Also, no signif- icant differences were observed in pre- and post-proce- dural blood pressure and heart rate. In 1997, a double-blind study was conducted by Fisher et al. comparing the effects of lidocaine gel and lubri- cant gel on pain during rigid cystoscopy. They inject- ed 300 ml of gel in the tract and cystoscopy began 20 minutes later. They showed that the injection of lido- caine gel was ineffective for reducing pain in women, but it significantly reduced the pain in men(1). In France, Thompson and colleagues conducted a study 1999 on the temperature of the gel, showing that cold lidocaine gel leads to more effective analgesia in patients during cystoscopy(2). In 2001, Derry Hurst suggested the use of 600 ml intravesical lidocaine gel for reducing the pain during cystoscopy(3). In 2005, Chen and his colleagues performed a rand- omized, double-blind trial in Taiwan on the analgesic effect of lidocaine gel during cystoscopy. They showed that lidocaine gel is a cost-effective analgesic method that dramatically reduces the need for analgesic use and hospitalization after cystoscopy(4). Shan et al., in China, performed a study in the same year on the effect of in- tracorpus spongiosum lidocaine injection before certain urological procedures including the endoscopic remov- al of stone and internal urethrotomy. They concluded that this anaesthetic could significantly decrease pain in 90% of the patients(5). In 2006, Shide and Turfan evaluated the effect of lido- caine gel on analgesia during endoscopic procedures in a retrospective study. He concluded that the best result is obtained when 20 to 30 ml of gel is injected into the urethra. It is better to inject slowly (at least 10 seconds) to cause less pain(6). A meta-analysis in 2009 showed the effect of lidocaine gel on reducing moderate to se- vere pain during flexible cystoscopy(7). Table 1. Comparison of pain, blood pressure and pulse rate between groups A and B. Variables GroupA (mean ± SD) GroupB (mean ± SD) P value Pain during procedure(number scale) 3.47 ± 3.03 4.64 ± 3.06 0.011 Pain during procedure (face scale) 2.26 ± 1.73 3.15 ± 1.97 0.008 Pain 5 minutes after procedure (number scale) 1.23 ± 1.51 1.65 ± 1.91 0.230 Pain 5 minutes after procedure ( face scale) 1.01 ± 1.17 1.36 ± 1.70 0.518 BP change, mmHg 0.4 ± 1.40 0.65 ± 1.49 0.271 BP before procedure, mmHg 13.96 ± 2.02 14.52 ± 2.30 0.324 BP after procedure, mmHg 14.38 ± 2.05 15.09 ± 2.23 0.094 PR before procedure 79.60 ± 12.430 78.29 ± 13.55 0.439 PR after procedure 79.54 ± 9.99 83.52 ± 15.07 0.402 Abbrebviations: Group A,lidocaine 2% injection plus intraurethral lidocaine gel group; group B,intraurethral lidocaine gel alone group; SD,standard deviation; BP,blood pressure; PR,pulse rate Subgroups GroupA (mean±SD) GroupB (mean±SD) P value cystoscopy Pain during procedure(number scale) 3.85 ± 3.20 4.85 ± 3.151 0.061 Pain during procedure (face scale) 2.49 ± 1.82 3.27 ± 2.09 0.060 Pain 5 minutes after procedure (number scale) 1.43 ± 1.61 1.86 ± 1.968 0.314 Pain 5 minutes after procedure ( face scale) 1.20 ± 1.23 1.52 ± 1.75 0.689 Urethral dilatation Pain during procedure(number scale) 2.28 ± 2.10 3.94 ± 2.73 0.074 Pain during procedure (face scale) 1.53 ± 1.17 2.78 ± 1.51 0.022 Pain 5 minutes after procedure (number scale) 0.61 ± 0.979 1.00 ± 1.60 0.606 Pain 5 minutes after procedure ( face scale) 0.41± 0.71 0.89 ± 1.49 0.568 Abbrebviations: Group A,lidocaine 2% injection plus intraurethral lidocaine gel group; group B,intraurethral lidocaine gel alone group; SD,standard deviation Table 2. Comparison of pain between groups A and B in cystoscopy and urethral dilatation subgroups. Lidocaine injection with gel in cystoscopy-Gooran et al. Vol 14 No 04 July-August 2017 4046 Ather et al. performed a nonrandomized study in 2009. They used intracorpus spongiosum lidocaine and seda- tion before optical urethrotomy and compared it with general or spinal anaesthesia. Sixteen out of 32 patients received 2 to 3 ml of 1% lidocaine into the glans pe- nis. In this group, 15 patients (94%) had no discomfort or pain. The anaesthetic effect lasted for an hour and it was satisfactory, without any complications. The visual analogue pain score was not different in the two groups. They concluded that urethrotomy using an intracorpus spongiosum lidocaine with sedation is as effective and safe as regional or general anaesthesia. This method is also cost-effective due to a shorter operative time(5). This study has some limitations. First, this is a sin- gle-centre study without a large sample size. Second, the patients in this study were observed for one hour and no one showed a major complication except some injection-related effects On the other hand, based on the literature review, this study is the first clinical double-blind study to evalu- ate the role of intracorpus spongiosum anaesthesia in urologic procedures. Another advantage of this study is the randomization and integration of the other factors related to pain. Intracorpus spongiosum anaesthesia can be used easily in the office without any reported com- plication. It is recommended that future studies are carried out with larger sample sizes. Higher doses of lidocaine are also recommended. This method can also be used in other endoscopic procedures such as urethral stone removal and internal urethrotomy. CONCLUSIONS Based on the findings of the present study, the injection of lidocaine 2% into the glans penis significantly re- duces pain perception immediately after cystoscopy or urethral dilatation compared to the use of intraurethral lidocaine gel alone. So, this method could be used as an effective way of pain control during cystoscopy reduc- ing the need of anaesthesia. ACKNOWLEDGEMENT This study was approved in Urology Research Center of Sina Hospital. The authors would like to thank Dr. Ayat ahmadi for statistical analysis, Mr Akbari and Miss Pa- joohan for their helps in procedures. CONFLICT OF INTEREST The authors report no conflict of interest. REFERENCES 1. Goldfischer ER, Cromie WJ, Karrison TG, Naszkiewicz L, Gerber GS. Randomized, prospective, double-blind study of the effects on pain perception of lidocaine jelly versus plain lubricant during outpatient rigid cystoscopy. J Urol. 1997;157:90-4. 2. Thompson TJ, Thompson N, O'Brien A, Young MR, McCleane G. To determine whether the temperature of 2% lignocaine gel affects the initial discomfort which may be associated with its instillation into the male urethra. BJU Int. 1999;84:1035-7. 3. Dryhurst DJ, Fowler CG. Flexible cystodiathermy can be rendered painless by using 2% lignocaine solution to provide intravesical anaesthesia. BJU Int. 2001;88:437- 8. 4. Chen YT, Hsiao PJ, Wong WY, Wang CC, Yang SS, Hsieh CH. Randomized double- blind comparison of lidocaine gel and plain lubricating gel in relieving pain during flexible cystoscopy. J Endourol. 2005;19:163-6. 5. Ather MH, Zehri AA, Soomro K, Nazir I. The safety and efficacy of optical urethrotomy using a spongiosum block with sedation: a comparative nonrandomized study. J Urol. 2009;181:2134-8. 6. Schede J, Thuroff JW. Effects of intraurethral injection of anaesthetic gel for transurethral instrumentation. BJU Int. 2006;97:1165-7. 7. Aaronson DS, Walsh TJ, Smith JF, Davies BJ, Hsieh MH, Konety BR. 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