MISCELLANEOUS Extracorporeal Shockwave Therapy Combined with Drug Therapy in Chronic Pelvic Pain Syndrome : A Randomized Clinical Trial Seyed Mansoor Rayegani1, Mohammadreza Razzaghi2 , Seyed Ahmad Raeissadat3, Farzad Allameh4*, Dariush Eliaspour1, Amirreza Abedi5 , Atefeh Javadi1, Amirhossein Rahavian5 Purpose: Chronic prostatitis/ chronic pelvic pain syndrome (CP/CPPS) is a nonspecific pelvic pain in the absence of signs of infection or other obvious local pathology for at least three of the last 6 months. Evidence for treatment approach is limited. So the aim of this study is to investigate the effect of extracorporeal shock wave therapy (ESWT) combined with pharmacotherapy in the treatment of CP/CPPS. Materials and Methods: In this randomized clinical trial, 31 patients with CP/CPPS were investigated in two groups: the intervention group (n=16) was treated with a combination of an alpha-blocker, an anti-inflammatory agent, a muscle relaxant and a short course of antibiotic in combination with 4 sessions of focused ESWT (a pro- tocol of 3000 impulses, 0.25 mJ/mm2 and 3 Hz of frequency). The control group (n=15) received the aforemen- tioned pharmacotherapy with 4 sessions of sham-ESWT . Follow-up was performed 4 and 12 weeks following ESWT by using the Visual Analogue Scale (VAS), International index of Erectile function (IIEF) 5, National Insti- tutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) and International Prostate Symptom Score (IPSS) questionnaires. Post void residual (PVR) urine and maximum flow rate (Qmax) were also assessed in both groups. Results: The patients mean age was 43.7 ±12.6 years. In both groups, the mean scores of NIH-CPSI (total and sub-domains) and VAS showed statistically significant improvements after 4 and 12 weeks compared to the base- line (P < .001). In the intervention group, IPSS (mean difference: 4.25) and Qmax (mean difference: 2.22) were also significantly improved (P < .001). There was a significant improvement in NIH-CPSI (mean difference: 1.1) and VAS scores (mean difference: 1.1) in the intervention group as compared to the control group (P < .01). Qmax, PVR and IIEF score were not statistically different in the two groups. Conclusion: ESWT in combination with pharmacotherapy could improve the treatment outcome in patients with CP/CPPS. Keywords: chronic pelvic pain syndrome; erectile dysfunction; extracorporeal shock wave therapy; pain manage- ment; prostatitis INTRODUCTION Chronic Prostatitis /Chronic Pelvic pain syndrome (CP/CPPS) is the most frequent urological disor- der in men younger than 50 and the third most common urological finding in men over 50 years old.(1) According to the national institute of health (NIH), chronic pelvic pain syndrome (CPPS) is a chronic or persistent pain that lasts 3 months in the last 6 months and is perceived in structures related to the pelvis which is associated with symptoms suggestive of lower uri- nary tract, sexual, bowel or pelvic floor dysfunction and causes negative emotional and cognitive consequences. 1Physical Medicine and Rehabilitation Research Center, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2Laser Application in Medical Sciences Research Center, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3Clinical Development Research Center of Shahid Modarres Hospital, Physical Medicine and Rehabilitation Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4Center of Excellence in Training Laser Application in Medicine, Shohada-e-Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 5Department of Urology, Shahid Beheshti University of Medical Sciences, Tehran, Iran. *Correspondence: Center of Excellence in Training Laser Application in Medicine, Shohada-e-Tajrish Hospital, Tajrish Sq., Tehran, Iran. Tel: +989123885545. Fax: +982122736386. Email: farzadallame@gmail.com. Received July 2018 & Accepted April 2019 (2,3) The prevalence of CPPS is between 3–10 % that af- fects nearly 15% of all urologic outpatient visits.(4,5) Despite its high prevalence and its impact on quality of life (QOL), the pathogenesis of the CPPS is hardly understood. Numerous etiologies are proposed includ- ing infection, pelvic floor hyperactivity, local chemical alterations, neurologic components (central sensitiza- tion), and perfusion disturbances.(6,7) It is important to exclude other genital and pelvic disorders present with pelvic pain before the diagnosis of CPPS.(8) The determination of the severity of the disease, its Urology Journal/Vol 17 No. 2/ March-April 2020/ pp. 185-191. [DOI: 10.22037/uj.v0i0.4673] progression and treatment response can be assessed by means of reliable questionnaires such as International Prostate Symptom (IPSS) Score and National Institutes of Health-Chronic Prostatitis Index (NIH-CPSI).(2,9,10) Unknown pathogenesis leads to limitations in the treat- ment of CPPS. The most common therapeutic approach- es are α-receptor blockers, like tamsulosin, antibiotics which cover gram negative germs, analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs) and 5-α- reductase inhibitors used as mono- or combination therapy.(11-13) The second-line treatment protocols include physical therapy, trigger-point massage, electromagnetic treat- ment, acupuncture, prostate massage, and intraprostatic injection of botulinum toxin A.(14,15) There are many challenging issues in the management of patients with CPPS, such as the possibility of treat- ment failure by monotherapy or pharmacological side effects in long-term use.(16) Although extracorporeal shock wave therapy (ESWT) has been successful for other indications such as or- thopedic pain syndromes,(17) there is limited evidence whether this approach is also effective for patients with CPPS. A number of mechanisms have been suggested including the increasing of local microvascularization, decreasing passive muscle tone, hyperstimulating no- ciceptors, interrupting the flow of nerve impulses, or influencing the neuroplasticity of the pain memory.(18,19) ESWT is an outpatient procedure without significant side effects that can be simply applied. According to the mentioned challenges in CPPS treat- ment and the fact that there is no conclusive data about the effectiveness of combining ESWT and drug thera- py, we conducted a sham-controlled randomized clin- ical trial to study the effects of ESWT and oral phar- macological treatment combination therapy in patients with CPPS, which, to the best of our knowledge, has not been performed before.(20) MATERIALS AND METHODS We performed this single-blind randomized controlled clinical trial from May 2017 to February 2018. Inclusion and exclusion criteria All patients with chronic prostatitis type IIIB/chronic pelvic pain syndrome who were referred to the urology clinic of Shohada-e-Tajrish hospital and met our inclu- sion criteria were enrolled in this study. The study in- clusion criteria were as follows: patients older than 18 years of age diagnosed with type IIIB prostatitis (crite- ria according to NIH classification)(3), patients with pain that lasted 3 months in the last 6 months without clear abnormalities upon urological examination and no ev- idence of bacteria in urinary and seminal fluid culture tests, and patients who were not addicted to drugs and narcotics. The exclusion criteria of this study included being un- der treatment by another method at the beginning of the study, other diagnoses such as varicocele, hernia or prostate cancer during workup, PSA > 4, bleeding diathesis, history of urethral stricture or hematuria or urinary tract infection in the last year. The diagnosis of patients was made by a single urol- ogist based on a comprehensive history and physical examination including digital rectal examination, PSA measurement, urine analysis and culture, semen analy- sis and two-cup test. A combination of an alpha blocker (tamsulosin 0.4mg daily), an NSAID (diclofenac sustained release 100mg daily), a muscle relaxant (baclofen 10mg/BD) for 12 weeks and a short term antibiotic (ofloxacin 300mg/BD for 2 weeks) were started for all patients. In this situa- tion, no one was deprived from the treatment. For each patient the questionnaires including IIEF5, IPSS and NIH-CPSI were completed and the degree of pain was assessed using VAS to achieve baseline char- ESWT in chronic pelvic pain syndrome-Rayegani et al. Figure 1. CONSORT 2010 Flow Diagram Miscellaneous 186 Vol 17 No 02 March-April 2020 187 acteristics by a blind investigator. We tried to have a consistent environment for partic- ipants and trained the participants well for rating the questionnaires to increase the reliability of our assess- ments. We also calculated the Cronbach’s Alpha for each questionnaire. Uroflowmetry was also done to obtain maximum flow rate (Qmax) and post void residual urine (PVR). We used PC based Wireless Uroflowmeter by MMS from Netherland. Table 1. Demographic and baseline data in both groups. Group N Mean Std. Deviation P Value Age (years) case 16 44.38 13.846 .77 control 15 43.07 11.708 Marriage status case 16 8(50%) 1.00 (number of married) control 15 7(53.3%) Ejaculation per week case 16 1.50 1.033 .4 control 15 1.80 0.941 Body Mass Index (Kg/m2) case 16 29.25 6.382 .98 control 15 29.20 6.656 Duration case 16 11.37 5.251 .95 (months) control 15 11.26 5.885 IIEF a 5 case 16 16.38 6.131 .66 control 15 15.47 5.153 IPSS b case 16 15.69 6.610 .90 control 15 15.40 6.208 NIH c pain part case 16 13.06 6.298 .44 control 15 14.67 5.052 NIH urination part case 16 4.75 2.817 .89 control 15 4.87 1.767 NIH QOL d part case 16 7.69 2.750 .44 control 15 8.33 1.759 NIH total score case 16 25.50 8.989 .42 control 15 27.87 7.259 PVR e (ml) case 16 14.7500 9.83531 .72 control 15 16.1333 11.84945 Qmax (ml/s) case 16 14.825 6.7752 .87 control 15 15.233 7.0605 VAS f case 16 6.44 1.263 .94 control 15 6.40 1.805 a IIEF: International Index of Erectile Function, b IPSS: International Prostate Symptom Score, c NIH: National Institute of Health, d QOL: Quality of Life, e PVR: Post Void Residue, f VAS: Visual Analog Scale Table 2. Mean difference of variables before and after treatment in intervention and control groups after 4 and 12 weeks Intervention group After 4 weeks After 12 weeks Mean difference P Value Mean difference P Value IIEF a 5 0.38 0.45 -0.81 .35 IPSS b 1.88 0.006 4.25 .0001 NIH c PAIN 4.25 0.0001 5.06 .0001 NIHURINE 2.25 0.0001 2.19 .001 NIHQOL d 3.75 0.0001 4.88 .0001 NIH Total 10.25 0.0001 12.12 .0001 Qmax -2.22 0.004 -1.8 .04 PVR e 2.88 0.056 4.2 .14 VAS f 3.81 0.0001 3.63 .0001 Control group After 4 weeks After 12 weeks Mean difference P Value Mean difference P Value IIEF 5 0.74 0.22 -0.80 .26 IPSS 0.73 0.6 1.40 .06 NIH PAIN 2.67 0.001 3.14 .0001 NIHURINE 0.87 0.003 0.87 .0001 NIHQOL 2.4 0.0001 2.33 .0001 NIH Total 5.94 0.0001 6.34 .0001 Qmax -0.59 0.17 0.65 .20 PVR 1.67 0.10 0.08 .92 VAS 1.73 0.0001 2.07 .0001 a IIEF: International Index of Erectile Function, b IPSS: International Prostate Symptom Score, c NIH: National Institute of Health, d QOL: Quality of Life, e PVR: Post Void Residue, f VAS: Visual Analog Scale. ESWT in chronic pelvic pain syndrome-Rayegani et al. Miscellaneous 188 Then using random number table, the participants were randomly divided into two groups using opaque enve- lopes to guarantee the allocation concealment. In this protocol all patients were blind about the future pro- cedure. Procedure In the intervention group, patients were treated by ESWT once a week for 4 weeks. Each time 3000 im- pulses, with 0.25 mJoules/mm2 and 3 Hertz of frequen- cy were delivered. After each 500 pulses, the probe position was changed. In this study, we used standard focused electromagnetic DUOLITH SD1 T-TOP by Storz Medical from Switzerland. The treatment was performed in supine position. In the sham group, the same protocol was applied for patients but the probe was turned off. Outcome assessment The primary outcomes were pain reduction and im- provement in urinary symptoms which were evalu- ated using VAS, NIHCPSI and IPSS questionnaires. The secondary outcomes included sexual performance which was assessed by IIEF5 questionnaire, objective urinary conditions (Qmax and PVR) and treatment complications. The follow-up assessments were done 4 and 12 weeks following the first ESWT session. The follow-up study included clinical examinations and filling the question- naires and taking a focused history of patients’ com- plaints by the same blind person who evaluated the participants at the beginning of the study, besides meas- uring Qmax and PVR by uroflowmetry. The study protocol was performed in accordance with the Declaration of Helsinki and approved by the Ethics Group N Mean Std. Deviation P Value IIEF a 5 case 16 16.00 5.177 .45 control 15 14.73 3.918 IPSS b case 16 13.81 4.679 .64 control 15 14.67 5.473 NIH c pain part case 16 8.81 3.351 .02 control 15 12.00 3.982 NIH urination part case 16 2.50 1.366 .01 control 15 4.00 1.690 NIH QOLd part case 16 3.94 1.340 .001 control 15 5.93 1.624 NIH total score case 16 15.25 4.282 .001 control 15 21.93 5.391 Qmax case 16 17.044 4.8814 .54 control 15 15.827 6.1762 PVR e case 16 11.8750 6.66208 .42 control 15 14.4667 10.63597 VAS f case 16 2.63 1.500 .001 control 15 4.67 1.447 a IIEF: International Index of Erectile Function, b IPSS: International Prostate Symptom Score, c NIH: National Institute of Health, d QOL: Quality of Life, e PVR: Post Void Residue, f VAS: Visual Analog Scale. Table 3. Comparison of outcomes between intervention and control groups after 4 weeks Group N Mean Std. Deviation P Value IIEF a 5 case 16 17.19 2.713 .34 control 15 16.27 3.327 IPSS b case 16 11.44 3.669 .93 control 15 14.00 4.536 NIH c PAIN part case 16 8.00 3.899 .01 control 15 11.53 3.980 NIH Urination part case 16 2.56 1.094 .003 control 15 4.00 1.363 NIH QOL d part case 16 2.81 1.047 .0001 control 15 6.00 1.309 NIH Total score case 16 13.38 4.703 .0001 control 15 21.53 4.533 Qmax case 10 14.600 3.8038 .40 control 12 16.333 5.4249 PVR e case 10 14.5000 4.30116 .80 control 12 13.5000 11.63459 VAS f case 16 2.81 1.167 .004 control 15 4.33 1.543 a IIEF: International Index of Erectile Function, b IPSS: International Prostate Symptom Score, c NIH: National Institute of Health, d QOL: Quality of Life, e PVR: Post Void Residue, f VAS: Visual Analog Scale. Table 4. Comparison of outcomes between intervention and control groups after 12 weeks. ESWT in chronic pelvic pain syndrome-Rayegani et al. Vol 17 No 02 March-April 2020 189 Committee of Shahid Beheshti University of Medical Sciences and it is registered on IRCT database with the following code: IRCT2017082635911N1. The in- formed consent was obtained after all patients were informed of the treatment methods and also about pub- lishing the data without disclosure of their names. It must be mentioned that there was no deviations from the study protocol in all phases of the project. Statistical Analysis The data were analyzed by SPSS (version 23). The bio- statistician was blind about treatment groups. Statistical analyses such as chi-square, paired t-test and independ- ent t-test were used. P value less than 0.05 implied sta- tistical significance. RESULTS Thirty-one male patients were randomly assigned to the intervention group (n=16) and control group (n=15). The CONSORT flow diagram is shown in Figure 1. The mean age of the patients in the intervention and sham groups were 44.3 ± 13.8 and 43.07 ± 11.7 years, respectively. The demographic data were summarized in Table 1. At baseline, the mean scores of IIEF5, VAS, IPSS and NIH-CPSI were not statistically different in the two groups. The mean scores of objective param- eters including Qmax (14.825 ± 6.77 versus 15.23 ± 7.06, p = .87) and PVR (14.75 ± 9.83 versus 16.13 ± 11.84, p = .72) were also similar in both groups. With respect to within-group data analysis, VAS score, total NIH-CPSI and all subdomains were significantly improved in both groups. The difference became sta- tistically significant 4 and 12 weeks after treatment. (Table 2). IPSS and Qmax were significantly improved in the intervention group (P < .006) but insignificant- ly improved in the sham group, 4 and 12 weeks after treatment. In addition, IIEF5 scores and PVR were not improved in either group at any follow-up time points. Regarding between-group analysis, the scores of NIH-CPSI subdomains including pain, urinary symp- toms and QOL became significantly different in the two groups at week 4. Total NIH-CPSI and VAS scores at this follow-up time point were also significantly differ- ent in favor of the intervention group(Table 3). After 12 weeks, the difference between the two groups was also noted and the mean ± SD NIH-CPSI total scores including pain, urinary symptoms and QOL sub- domains were 13.38 ± 4.70 in the intervention group and 21.53 ± 4.53 in the sham group (P = .0001). VAS score was different in the two groups and the mean was 2.81 ± 1.16 versus 4.33 ± 1.54 in the intervention and control group, respectively (P = .004). But the mean scores of Qmax (14.6 ± 3.80 versus 16.33 ± 5.42, P = .40) and PVR (14.5 ± 4.30 cc versus 13.50 ± 11.63 cc, P = .80) were not significantly different. Also, the mean of IIEF5 (17.19 ± 2.71 versus 16.27 ± 3.32, P = .34) and IPSS (11.44 ± 3.66 versus 14 ± 4.53, P = .93) were not different in the two populations (Table 4). There were only 18% (n = 4) and 13% (n = 2) loss to follow-up in intervention and control groups respective- ly, yet all the questionnaires were filled by interview on phone and only uroflowmetry was not performed. In this study, four patients in the intervention group ex- perienced minor complications that included transient hematuria and hematospermia which were not statisti- cally and clinically noteworthy. DISCUSSION Our study showed that ESWT and drug therapy could improve urinary symptoms, pain and QOL of patients with CPPS. Numerous studies in other fields of medicine such as cardiology and orthopedics have shown that ESWT is effective and has no significant side effects.(17,21) This issue was confirmed in the present study. Furthermore, ESWT is effective to alleviate pain and help heal tissue. This can be explained by local muscle relaxation and ESWT–induced neovascularization.(22,23) A randomized double-blind study of ESWT in patients with CPPS performedby Zimmermann et al.(19) showed that all outcome parameters improved significantly in the treatment group at month 3 (IPSS: 25% decrease; IIEF: 5.3% increase; NIH-CPSI: 17% decrease; VAS: 50% decrease), with no improvement in the sham-treat- ment group. This study was the first study to recommend level 1 evidence for ESWT in patients with CPPS.(19) In the study of 80 CPPS patients,(24) there was a signif- icant improvement in pain, QOL and total NIH-CPSI scores in the ESWT group compared to the sham group. In our study, an improvement in symptoms was ob- served in both intervention and sham groups that can be in line with the sham effect and also the medications used in both groups. However, the difference became significant at weeks 4 and 12 after treatment for VAS and NIH-CPSI total and subdomain scores in favor of ESWT. Yet IPSS was not significantly different in each follow-up time. In most studies(23,25,26), identical to the present research, focused ESWT was used, with the exception of only one study.(27) In this randomized controlled study, a ra- dial shock wave device was used in CPPS patients and the outcomes were compared with the second group in which pharmacological treatment was administrated. A significant improvement of pain and QOL was reported in the first group. In the present study, Qmax and PVR were not signif- icantly different in the two groups in each follow-up time, while the study conducted by Pajovic et al.(25) showed statistically significant improvement in both PVR and Qmax after receiving a combination of tri- ple drug therapy and ESWT, which could be due to the longer duration of treatment (12 sessions of ESWT, once-weekly) Although, in this study, the mean score of IIEF at the baseline was similar to some previous studies, there were no significant changes in our follow-up study, contrary to the findings of above-mentioned studies. (19,28,29) The average of follow-up in most studies was 12 weeks after ESWT(19,24,26,27) but some studies extended their follow-up ranging from 24 weeks to one year.(25,29,30) Moayednia et al.(30) showed that at week 24 of fol- low-up, the mean scores of pain, urinary symptoms, QOL and total NIH-CPSI score were not statistically different from baseline in the ESWT group. While in another study,(29) the efficacy of shock wave was proven for one year after treatment. It seems that further studies are needed to determine its long-term efficacy. Although our data looks very promising, some limiting factors in our study need to be considered: the study pe- riod of only 3 months is short, therefore, the durability of this approach is unknown. ESWT in chronic pelvic pain syndrome-Rayegani et al. The lack of side-effects specific to ESWT make it possible to repeat the ESWT cycle at any time. In the future, it might be possible to significantly extend the treatment sessions possibly to achieve a long-lasting treatment effect. CONCLUSIONS ESWT is an outpatient and easy procedure that in com- bination with pharmacotherapycould improve treatment outcomes in patients with CP/CPPS. ACKNOWLEDGEMENTS We would like to thank the Laser Application in Medi- cal Sciences Research Center personnel for their coop- eration and compassion. 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