The therapeutic effect and safety profile of extracorporeal shockwave therapy in treatment of chronic prostatitis/chronic pelvic pain syndrome: a systematic review

Evidence acquisition

Search methodology and criterion for selection

The present systematic review was conducted using the guidelines established by the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA). A comprehensive review of the literature was conducted by searching three different databases, which are PubMed, Scielo, and Science Directs. The search was carried out using the terms “Chronic Prostatitis” OR “Chronic Pelvic Pain Syndrome” AND “Extracorporeal Shockwave Therapy”. The keywords used were the same across all databases. The scope of the search was restricted to scholarly articles that were published during the past ten years. The articles included in this review were chosen according to specific criteria for inclusion. These criteria covered articles written in English, articles that examined the effectiveness and clinical procedure of Extracorporeal Shockwave Therapy in relation to Chronic Prostatitis or Chronic Pelvic Pain Syndrome, and original studies that had easily accessible full-text articles. This article excludes other sorts of writings, such as letters to the editor, reviews, and editorials, that discuss prostatitis types other than chronic pelvic pain syndrome (CPPS).

The two investigators (M and IAD) had conducted the initial screening from the titles and abstracts independently. Subsequently, a comprehensive evaluation was conducted on the whole texts of publications that were considered possibly necessary, as well as those for which a conclusive determination could not be reached just based on the abstract. The search approach employed in this study resulted in a total of 67 findings across the three aforementioned databases. The author screened every abstract to find articles. Consequently, 59 articles were excluded, leaving 8 articles to be included in this review for further investigation.

Quality evaluation

The quality of each randomized controlled study was assessed using an instrument by Sterne et al.⁸ In order to evaluate the potential for bias in experimental research, an assessment was conducted across six domains that pertain to the internal and external validity of these investigations. These domains include the selection of the reported result, measurement of the outcome, missing outcome data, randomization procedure, deviation from intended treatments, and overall bias (Figure 1). A score was assigned to each domain, namely, yes, probably yes, probably no, and no. The studies were categorized into three levels of bias risk, namely low, moderate, and high, according to the overall assessment made by the algorithm for each randomized controlled trial research. In the context of cohort studies, the evaluation encompassed seven distinct categories, namely: participation selection, confounding bias, deviation from intended interventions, intervention classification, outcome measurement, and selection of reported results. A score was assigned to each domain, namely yes, probably yes, probably no, and no. The studies were categorized into four groups based on the algorithm’s comprehensive assessment, indicating varying levels of bias: low, moderate, serious, and critical.

Figure 1. Risk of bias.

Data collection

The data from the chosen articles were extracted by two authors (M and IAD) separately. This extraction process involved utilizing a standardized form to collect information such as the publication year, authors, clinical protocol, efficacy of Extracorporeal Shock Wave Therapy (ESWT), and its impact on chronic prostatitis or chronic pelvic pain syndrome. The collected data was then assessed using the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) scoring system. Any inconsistencies in the retrieved data were resolved by discussion and consultation of the original article in order to reach an agreement.

Patient characteristic

All included studies in this review only recruited men older than 18 year of age that have been diagnosed with CPPS/Group III prostatitis. Despite CPPS varies in 2 subgroups (IIIA and IIIB) most studies only include prostatitis group IIIB and only 2 studies include both IIIA and IIIB group of prostatitis. Baseline CPSI Score for total domain ranges from 25 to 31 points with different follow up timings in each study (ranging from 1 month to 12 months after ESWT treatment).

Clinical protocol

As listed in Table 1, the protocol that mostly used was electromagnetic energy generator with 0.25 mJ/mm² energy flow density, 3000 pulses counted and 3 Hz of frequency once a week. Every study that stated in this review had a significancy in statistic (p<0.05). Electropneumatic protocol used in 1 cohort study that have been published by Ghazi et al. using Roland-Pagani brand from Italy with 2500 pulses and 3 Hz of frequencies that generated 0.25 mJ/mm² energy in 1 session of ESWT.⁹ That study conduct 1 session of ESWT per week and lasted for 4 sessions. The result was the ESWT treatment statistically significant to reduce the symptoms of CP/CPPS by decreasing the CPSI score in most domain as the time followed up progressively (p-value<0.05).⁹ Meanwhile piezoelectric machine was used in only 1 RCT study using Lubisone brand machine from South Korean with 3000 pulses and 3 Hz of frequencies that generate 0.25 mJ/mm² per session. This study conducted 1 session per week for along 12 sessions and resulted in statistically significant reducing the CPSI score in all domain compared to the placebo (p-value<0.05).¹⁰ On the other hand, one paper from Mykoniatis et al. comparing 2 different protocol for ESWT in CP/CPPS. They compared between group of 1 session per week and 2 sessions per week for overall 6 sessions applied and resulted in statistically insignificant for both groups compared (p-value>0.05) but statistically significant compared to the baseline (p-value< 0.05).¹¹

Clinical improvement

From 8 studies that have been yielded, 2 of them are cohort and the rest are clinical trial. 2 cohort studies showed that the clinical improvement were present for all time follow up CPSI scoring regard from the baseline for all domain (p-value<0.05). Otherwise, study from Zhang et al., stated that there was no significancy between the combination of ESWT and oral triple therapy group and oral triple therapy medication group without ESWT intervention.¹² All of the study result containing the clinical improvement by CPSI Scoring summarized in Tables 2, 3 and 4.

ESWT machinery

Pressure waves are well-established oscillating waves that have The capacity for propagation across various mediums such as gases, liquid and solid. As mentioned before, shockwaves are a form of pressure wave characterized by nonlinearity and a brief duration of rise time, often lasting for a maximum of 10 seconds. The negative and positive phases of shockwaves have distinct outcomes on the interfaces between different tissues characterized by differing densities. During the positive phase, it is possible for high-pressure shockwaves to either impact an interface and undergo reflection or traverse through it and gradually undergo absorption. In the negative phase, commonly mentioned to as the tensile phase, the shockwave induces cavitation at the interfaces of the tissue, leading to the making of air bubbles. Subsequently, the bubbles undergo implosion at a significant velocity, so producing a further series of shockwaves or fluid microjets.¹³

There are two distinct categories of ESWT shockwaves: Focused ESWT (FSWT) and Radial ESWT (RSWT). FSWT is distinguished by the creation of a pressure field that converges at certain depths inside particular tissues, resulting in reaching a level of maximal pressure at the adjustable focus. In the context of medical practice, the utilization of both concentrated shock waves and radial pressure waves is seen. Radial pressure waves are sometimes denoted as radial shock waves, however it is important to note that this terminology needs to align with the precise use in the field of physics. Shock waves and pressure waves show differences not only in their generating mechanisms, but also in the physical parameters often employed and the depths of therapeutic tissue penetration they may attain. Meanwhile FSWT treat at certain waves, RSWT apply the linear effect on every layer of the tissue. Therefore, FSWT are proposed to have a role at urologic intervention including CP/CPPS while RSWT are proposed to have a role at musculoskeletal problem.

The energy generator that utilized to make RSWT are different from FSWT. RSWT utilized electropneumatic (EP) to produce wave meanwhile FSWT utilize 3 type of generators: Electrohydraulic (EH), Electromagnetic (EM), and Piezoelectric (PE)

The production of focused shockwaves in water is facilitated by the comparable acoustic impedance of water and biological tissue. Therefore, the process of reflection is diminished. Electrohydraulic pulse (EP), electromagnetic pulse (EM), and piezoelectric effect (PE) all employ water as a medium for generating intense shockwaves, hence exhibiting a similarity. However, there is a clear distinction in the instant when shockwaves are formed. Electro-pneumatic (EP) generators are capable of producing shockwaves instantly following the spark gap, in contrast to electromagnetic (EM) and piezoelectric (PE) generators which exhibit a delay in the nanosecond range due to wave focalization.¹³

Although the clinical efficacy of the treatment, the underlying mechanism of action of ESWT remains unclear. During the year of 1997, Haupt put up four potential pathways for the stages of tissue response to ESWT.¹³

In CP/CPPS itself, the main therapeutic pathway of ESWT are in both physical and physiochemical phase which hyperstimulate the nociceptor and release the muscle stiffness to alleviate symptoms in all domain of CPSI scoring.⁷

ESWT treatment protocol

The machinery in this systematic review of focused ESWT separated into 3 kind of energy generator (EP, EM, and PE). All of the 3 machine shared the same amount of shockwave energy with different protocols. Thus, every ESWT operator need to know the basic protocol that are usually used in CP/CPPS for each machine regardless the brand of the machine itself. Ghazi et al. utilized Roland Pagani ES.WT four sessions weekly (2500 Pulses, energy flow density of 0.25 mJ/mm², and 3Hz).⁹ Meanwhile PE machine that was used by Pajovic et al. used Lubisone machine 12 sessions weekly (3000 pulses, 0.25 mJ/mm² of energy flow density and 3 Hz).¹⁰ And lastly EM machine using Storz and Cenowave machine, have differed protocol in some studies for 4-6 sessions weekly (3000 pulses, 0.096-0.25 mJ/mm² of energy flow density and 3-10 Hz).^12,14–17 Interestingly, one study from Mykoniatis et al., stated that there were no significant differences of CPSI result between undergoing ESWT treatment once a week or twice a week. However all ESWT clinical protocols in this systematic review have shown significant improvement of CPSI scores compared to baseline.¹¹

ESWT effect on pain domain

From 3 different type of ESWT machinery (EP, EM, PE), all of them shared the same effect on pain domain from CPSI scoring system. Study from Ghazi et al., using EP Roland Pagani ES.WT machine showed significant improvement of pain symptom. The peak of the effect was reached for 6 months and lasted for 12 months after a month of ESWT treatment under specified protocol.⁹ Another study by Pajovic et al., utilized PE machine from Lubisone also demonstrated significant improvement compared to placebo 3 months and 6 months after 12 sessions of ESWT treatment.¹⁰ EM machine, the most frequently used in the study included, also showed another improvement in pain symptom. Kim et al. stated in their study that their machine (Cenowave medical) had improved their patients pain symptom in 1 month compared to placebo group.¹⁷ Pain improvement also recorded by Rayegani et al. with their Storz Medical EM machine 1 month and 3 months after 4 sessions of ESWT. Compared to placebo, the ESWT group had significant improvement in 1 month until 3 months of observations.¹⁴ Afterall, from the studies included in this systematic review, ESWT effect the pain relieve effect can last until 12 months. 3 different energy generator (EP, EM, PE) have similar effect regards the differences of the protocol that have been used in the last 10 years studies.

ESWT effect on urinating domain

In this systematic review we found 1 study stated that there was no significant improvement in urinating domain of CPSI. EM Cenowave medical that was utilized by Kim et al. showed no improvement after 1 months of observation in urinating domain. Small sample sized that was observed during the study and the length of follow up that only observed for 1 month may be the cause of this negative result.¹⁷ Meanwhile, the others showed statistically significant improvement in urinary symptoms after ESWT therapy. Ghazi et al. EP Roland Pagani ES.WT showed significant improvement even 12 months after 4 sessions of ESWT therapy compared to the.⁹ Another study from Pajovic et al., using PE Lubisone Machine protocol stated that ESWT enhanced the condition of the related symptom compared to the placebo.¹⁰ Ultimately another EM machine by Storz medical also presented significant improvement in 1 month and reached its peak in 3 months after 4 sessions of ESWT therapy.¹⁴ Despite single contradictive result from Kim et al., most of study showed significancy in rectify the urinary symptom in CP/CPPS patients. Therefore, bigger sample size and longer observation are needed to be done for further research.

ESWT effect on quality of life domain

The Quality of Life is one of three domain that was comprised in CPSI scoring system. It showed the satisfaction of patient with their condition subjectively. All of the study yielded in this review stated that the patient satiety in quality of life domain had been improved by the treatment of ESWT. EP Roland Pagani ESWT Machine showed significant improvement even in 1 month until 12 month after 4 sessions of ESWT treatment compared to the baseline.⁹ PE Lubisone machine also stated similar outcome that 4 sessions of ESWT treatment enhanced the quality of life of CP/CPPS patients with and last for 6 months.¹⁰ Likewise, an improvement to the quality of life had been reported from all EM machine studies, either by Storz or Cenowave medical. Kim et al. Cenowave medical showed improvement compared to placebo, and Rayegani et al. Storz medical showed positive result for the exact 1 month after ESWT protocol treatment^14,16,17

ESWT effect on total domain

Despite the contradictive result from urinating domain by Kim et al., the overall calculation of CPSI domain showed an improvement from the studies included in our review (2 cohort studies and 3 RCT studies) that analysed each domain of CPSI. Another 2 studies from Sakr et al. and Wu et al., had demonstrated similar outcomes. Sakr et al. had found a significant improvement in total CPSI domain after 4 sessions of ESWT treatment compared to placebo within 12 months of observations.¹⁶ Meanwhile Wu et al., reported improvement only after 8 sessions of ESWT treatment resulted compared to the placebo.¹⁵ Otherwise, 1 study from Zhang et al. did not observe any significant improvement after 8 sessions of ESWT treatment.¹² This phenomenon may be caused by the exclusion of 10 relapsing patients in this particular study. Other possible explanations for these findings may also be explained by the different protocol that have been used by Zhang et al. (10 Hz of Frequency with 0.18-0.2 mJ/mm² of energy 1 session a week vs 3-4 Hz of frequency, 0.25 mJ/mm² of energy flow density in other EM ESWT studies). Thus, the standardize protocol for ESWT machine need to be established for each energy generator used.¹²

These result from 8 studies that have been yielded, all 7 studies demonstrate the efficacy of ESWT treatment with 3 kind of machinery that available worldwide. The efficacy and safety of ESWT treatment for CP/CPPS patients had showing a good outcome with less adverse effect for the CP/CPPS patients in the maximum of 12 months of observation. The limitations of this systematic review is the restricted variety of energy generators with the lack of openly registered protocols. The lack of adherence to protocols and registration may give rise to the potential of biases and compromise the accuracy and transparancy of the review. This presents the risk of selective in the absence of pre-established protocols, which may later affect the validity of the findings.

Longer additional studies with longer observation are needed to be done in the future research in order to evaluate the efficacy and safety protocol of ESWT on CP/CPPS. Even with the benefit of ESWT usage for CP/CPPS, the standardize protocols are needed to enhance the outcome of the patients. The variety of machine and brand are sometime confuse the operator to set the protocol for each machine, and moreover, some of the brands are not displaying the energy flow density on its devices. Therefore, this review is comparing the protocol and the outcome that has been observed for the last 10 years. Hopefully, this review can be a suggestion and a guidance for many clinician or researcher to be applied in daily practice or to be an insight for further research.

Registration and protocol

The evaluation was undertaken without previous registration and without any registered processes.