*Article* **Extracorporeal Shockwave Therapy (ESWT) Alleviates Pain, Enhances Erectile Function and Improves Quality of Life in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome**

**Wen-Ling Wu 1,2, Oluwaseun Adebayo Bamodu 1,3,4, Yuan-Hung Wang 4,5, Su-Wei Hu 1,2,5, Kai-Yi Tzou 1,2,6, Chi-Tai Yeh 4,7 and Chia-Chang Wu 1,2,6,\***


**Abstract:** Purpose: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), affecting over 90% of patients with symptomatic prostatitis, remains a therapeutic challenge and adversely affects patients' quality of life (QoL). This study probed for likely beneficial effects of ESWT, evaluating its extent and durability. Patients and methods: Standardized indices, namely the pain, urinary, and QoL domains and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL\_US were employed in this study of patients with CP/CPPS who had been refractory to other prior treatments (*n* = 215; age range: 32–82 years; median age: 57.5 ± 12.4 years; modal age: 41 years). Results: For CP symptoms, the mean pre-ESWT NIH-CPSI total score of 27.1 ± 6.8 decreased by 31.3–53.6% over 12 months after ESWT. The mean pre-ESWT NIH-CPSI pain (12.5 ± 3.3), urinary (4.98 ± 2.7), and QoL (9.62 ± 2.1) domain scores improved by 2.3-fold, 2.2-fold, and 2.0-fold, respectively, by month 12 post-ESWT. Compared with the baseline IPSS of 13.9 ± 8.41, we recorded 27.1–50.9% amelioration of urinary symptoms during the 12 months post-ESWT. For erectile function, compared to pre-ESWT values, the IIEF-5 also improved by ~1.3-fold by month 12 after ESWT. This was corroborated by EHS of 3.11 ± 0.99, 3.37 ± 0.65, 3.42 ± 0.58, 3.75 ± 0.45, and 3.32 ± 0.85 at baseline, 1, 2, 6, and 12 months post-ESWT. Compared to the mean pre-ESWT QoL score (4.29 ± 1.54), the mean QoL values were 3.26 ± 1.93, 3.45 ± 2.34, 3.25 ± 1.69, and 2.6 ± 1.56 for months 1, 2, 6, and 12 after ESWT, respectively. Conclusions: This study shows ESWT, an outpatient and easy-to-perform, minimally invasive procedure, effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with refractory CP/CPPS.

**Keywords:** chronic prostatitis; chronic pelvic pain syndrome; extracorporeal shockwave therapy; ESWT; NIH-CPSI; EHS; IIEF-5; QoL

#### **1. Introduction**

Prostatitis affects an estimated 8.2% of the global population and remains a major health issue [1]. Added to the therapeutic challenge it poses to physicians, prostatitis adversely affect patients' quality of life (QoL) [2] and causes patients substantial economic

**Citation:** Wu, W.-L.; Bamodu, O.A.; Wang, Y.-H.; Hu, S.-W.; Tzou, K.-Y.; Yeh, C.-T.; Wu, C.-C. Extracorporeal Shockwave Therapy (ESWT) Alleviates Pain, Enhances Erectile Function and Improves Quality of Life in Patients with Chronic Prostatitis/Chronic Pelvic Pain Syndrome. *J. Clin. Med.* **2021**, *10*, 3602. https://doi.org/10.3390/jcm 10163602

Academic Editor: Du Geon Moon

Received: 15 July 2021 Accepted: 10 August 2021 Published: 16 August 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

constraint [3]. The National Institutes of Health (NIH) clinical syndromes-based classification system divides prostatitis into four categories: namely, category I, which includes acute systemic infection and replaces the so-called 'acute bacterial prostatitis'; category II, which replaces the erstwhile 'chronic bacterial prostatitis', and comprises recurrent urinary tract infection (UTI) in men with prostatic bacterial presence between infections; category III for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), evidenced by chronic pelvic pain with no known alternative attributable pathology; and category IV for asymptomatic prostatitis based on biopsy- or semen analysis-confirmed inflammation [3–5].

Protracted painful prostatitis, herein termed CP/CPPS, affects over 90% of patients with symptomatic prostatitis [6], and is characterized by persistent or recurring pain/ discomfort in the pelvis for at least 3 of the last 6 months, often accompanied by lower abdominal pain; painful ejaculation; genital pain; lower urinary tract symptoms (LUTS) such as hesitancy, straining, feeling of incomplete bladder emptying, poor or intermittent stream, dribbling, prolonged micturition, urgency, frequency, or nocturia; psycho-social impairments; and erectile/sexual dysfunction [3–6].

Over the last six decades, CP/CPPS, attributed to infection, inflammation, impaired urothelial integrity and function, endocrine imbalance, autoimmunity, voiding dysfunction, or neuropsychological factors [7,8], has remained a 'diagnosis of exclusion' with currently unclear or inexact underlying cause, thus stimulating interest and concerted research effort to demystify its etiology and unravel probable underlying molecular mechanisms. Recently, *Trichomonas Vaginalis* infection has been suggested as a probable pathoetiologic factor in CP/CPPS because of its complicity in chronic persistent prostatic infection and prostate epithelial cell inflammation [9]. Being able to cause inflammation by adhering to normal prostate epithelial cells [9,10], the association of *T. Vaginalis* with benign prostate hyperplasia (BPH) and prostate cancer is also currently being investigated [11,12]. However, the effect of *T. Vaginalis* on the development of chronic prostatitis remains unclear [13,14].

Despite advances in diagnostic and therapeutic approaches based on our evolving understanding of the CP/CPPS etiopathology, there is no international consensus-based approved single agent therapy with proven high efficacy against this syndrome [15], thus, the adoption of multi-modal approaches to treating CP/CPPS [16] such as the 'three As'. The 'three As' modality consists of α-blockers, antibiotics, and/or anti-inflammatory/immune modulation therapy. There is mounting evidence supporting the therapeutic efficacy of the three As in some patients with CP/CPPS [17]. The magnitude of effect and the disproportional mean decrease in the NIH Chronic Prostatitis Symptom Index (NIH—CPSI) and response rates in treatment groups in comparison to placebo groups suggest the superiority of directed multi-modal therapy over monotherapy, and advocate consideration of these agents for optimal management of patients with CP/CPPS [17]. Alternatively, phytotherapies, including quercetin, Cernilton, Eviprostat/pollen extract, and pentosane polysulfate [17,18], as well as non-pharmacological therapies such as acupuncture and extracorporeal shockwave therapy (ESWT), have also shown some efficacy in the treatment of CP/CPPS [8].

The UPOINTS algorithm, formed by addition of the sexuality (S) component to the original UPOINT system consisting of urinary domain (U), psycho-social (P), organ-specific (O), infection (I), neurological (*n*), and muscle tension and tenderness (T) domains, helps stratify patients into clusters of homogeneous clinical presentation, identifies recognizable phenotypes, and proposes specific treatment plans [19]. Accruing evidence indicates that treatment of patients consistent with this complex multi-modal disease phenotypebased therapeutic approach elicits clinically appreciable amelioration of CP/CPPS symptomatology in many patients, with the addition of second-line therapeutics such as 5 phosphodiesterase inhibitors, antidepressants, muscle relaxants, and anxiolytics to help elicit satisfactory treatment response in patients with sub-optimal response to initial firstline therapy [20]. There are reports associating the UPOINTS algorithm with clinical improvement in 75–84% of CP/CPPS cases [5,19–21].

As already mentioned, non-pharmacological therapies are also touted as effective against CP/CPPS [8,22]. ESWT is one such non-pharmacological treatment modality [22]. ESWT is well-known and widely used in urological clinics to treat Peyronie's disease, erectile dysfunction (ED), and chronic pelvic pain [23]. Zimmermann R. et al. first reported the use of ESWT for treating CP/CPPS in 2009. Their seminal report demonstrated the ease and safety of ESWT, as well as showed that all patients with CP/CPPS completed their treatment without complications and that follow-up was uneventful, with all treated patients exhibiting marked amelioration of pain, improved QoL, and better voiding conditions following ESWT, compared with progressive deterioration in the placebo group [24]. It has been suggested that the observed post-ESWT improvement in CP/CPPS may be due to "reducing passive muscle tone, hyperstimulating nociceptors, interrupting the flow of nerve impulses, or influencing the neuroplasticity of the pain memory" [25].

Despite these touted beneficial effects of ESWT on CP/CPPS, there are suggestions that its therapeutic effects may be short-lived, with tendency to decrease in month 6 of follow-up [23]. However, contradictory results on the effect of ESWT on CP/CPPS abound, especially with a dearth of long-term follow-up. Considering the short duration (3 months) of the premier ESWT study and the unusual lack of placebo response in the control group, as rightly posed by Marszalek M [25], outstanding questions linger regarding (i) suitable patient demographics or selection criteria for the treatment, (ii) the probable potentiating effect of previous treatment strategies, and (iii) the unclear durability of treatment benefit for lack of longer term effect data [23–25]. Thus, the present study evaluates the therapeutic effect of ESWT on CP/CPPS patients with prior treatment failure.

#### **2. Methods**

#### *2.1. Patients*

This single-center, prospective, single-arm cohort study was performed from September 2016 to January 2018 at the Shuang Ho Hospital, Taipei Medical University, New Taipei, Taiwan. A total of 215 patients with established diagnosis of CP/CPPS, non-inflammatory type (NIH type IIIb prostatitis), were included in our study. The study was approved by Taipei Medical University-Joint Institutional Review Board (Approval No.: N201712069), and written informed consent was obtained from all the enrolled patients. The study protocol was compliant with the Declaration of Helsinki.

Enrolled patients were seen in the outpatient settings. Diagnosis was established after thorough history-taking, physical examination, and screening with the following examinations: (i) urine analysis, (ii) urine culture, (iii) semen analysis, (iv) semen culture, (v) nucleic acid amplification test (NAAT) for *T. Vaginalis*, (vi) NAAT for *Chlamydia trichomatis*, (vii) blood test, including complete blood count/differential count, and C-reactive protein (CRP), (viii) prostate ultrasound, and (ix) kidney, ureter, and bladder (KUB) radiography.

#### *2.2. Inclusion and Exclusion Criteria*

Inclusion criteria were as follows: patients (i) aged 18 or above, (ii) diagnosed with CP/CPPS, (iii) suffered prostatitis-like symptoms for at least the last 6 months with no identifiable cause, (iv) refractory to administered medical therapies for at least the last 6 months. The exclusion criteria included (i) anatomical abnormalities of the genitourinary system, (ii) urinary tract or perineal region infection, (iii) cancer of the genitourinary system, (iv) prostate specific antigen >4, and (v) major surgery of the pelvic organs, including the prostate or rectum.

#### *2.3. ESWT Protocol*

All patients were treated in the dorsal recumbent position with perineal ESWT once a week for 6 consecutive weeks with a protocol of 3000 pulses at an energy of 0.25 mJoule/mm<sup>2</sup> and a frequency of 4 Hertz (Hz) using DUOLITH® SD1 (Storz Medical AG, Tägerwilen, Switzerland). Probe position was changed after every 500 pulses to broaden the therapy effect field, induce re-perfusion of the prostate, improve the hemodynamic profile of the prostatic artery, and forestall probable procedure-associated side-effects, such as, itchy or painful dysesthesia, ecchymosis, and petechiae. One cycle consisted of 6 sessions. The DUOLITH® SD1 is a mobile shockwave therapy apparatus with a SEPIA® hand-piece for ease of manipulation and positioning to facilitate focused shock waves.

#### *2.4. Evaluation of Outcome*

The primary outcomes of the present study, namely, pain reduction and amelioration of urinary symptoms, were evaluated using the NIH-CPSI, International Prostate Symptom Score (IPSS), and American Urological Association Quality of Life due to Urinary Symptoms (AUA QOL\_US), while improved sexual function, being the secondary outcome, was assessed using the International Index of Erectile Function (IIEF), and Erection Hardness Score (EHS). All questionnaires were completed after detailed explanation during clinic visits (i) before commencing ESWT, (ii) after the third ESWT session, (iii) a week after the sixth ESWT session, (iv) 1 month, (v) 2 months, (vi) 6 months, and (vii) 12 months after the last ESWT session. Aside from ESWT treatment, all patients with concomitant *T. vaginalis* infection (*n* = 19) were given a single dose of 2 g Metronidazole. None of the enrolled subjects underwent transurethral resection of the prostate (TURP) during follow-up, nor did any receive other therapies concomitantly with ESWT.

#### *2.5. Statistical Analyses*

All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 25.0 (IBM Corp. Released 2017, Armonk, NY, USA: IBM Corp). For randomly missing data, we used the pairwise deletion (also known as the 'available case analysis') by deleting any case with missing variables required for a specific analysis, but including such cases in analyses where all required variables were present. Pearson's chi-square (χ2) test was used to determine the relationship or association between categorical variables. The paired sample t-test was used for comparing two dependent sample means, while the independent t-test was used to compare independent sample means. *p* values ≤ 0.05 were considered statistically significant.

#### **3. Results**

The present study evaluated the effect of ESWT on pain, erectile function, and QoL in patients with CP/CPPS (*n* = 215) using standardized evaluation indices, namely the pain domain, urinary domain, QoL domain, and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL\_US. Participants were aged 32–82 years (mean: 57.1 ± 12.41 years; median: 57.5 ± 12.41 years; modal age: 41 years).

For CP symptoms, the mean NIH-CPSI pain, urinary, and QoL domains, as well as total score before ESWT were 12.53 ± 3.25, 4.98 ± 2.72, 9.62 ± 2.06, and 27.10 ± 6.81, respectively. Compared to these baseline values, the mean NIH-CPSI total scores decreased by 31.3%, 37.3%, 35.7%, and 53.6% at 1, 2, 6, and 12 months after ESWT administration, respectively (Supplementary Table S1). Per component, we observed a 2.3-fold, 2.2-fold, and 2.0-fold improvement in the CPSI pain, urinary and QoL domains, respectively, by month 12 post-ESWT (Figure 1; also see Supplementary Table S1).

**Figure 1.** Extracorporeal Shockwave Therapy and Chronic Prostatitis Symptom Index (CPSI). Notched box-and-whiskers graphs showing the time-phased effect of extracorporeal shockwave therapy using the (**A**) urinary domain, (**B**) pain domain, (**C**) quality of life, and (**D**) total score over a period of 12 months. \*\* *p* < 0.01, \*\*\* *p* < 0.001.

For erectile function, the IIEF-5 also improved significantly after ESWT, as demonstrated by mean IIEF-5 scores of 18.43 ± 6.34 (1.1-fold), 20.42 ± 5.59 (1.3-fold), 20.25 ± 5.94 (1.3-fold), and 18.65 ± 6.85 (1.2-fold) at months 1, 2, 6, and 12 respectively, compared to the mean IIEF-5 score of 15.82 ± 7.70 before ESWT (Supplementary Table S1). This was corroborated by the improved EHS of 3.37 ± 0.65, 3.42 ± 0.58, 3.75 ± 0.45, and 3.32 ± 0.85 at 1, 2, 6, and 12 months post-ESWT, respectively, compared to baseline (3.11 ± 0.99) (Figure 2A,B; also see Supplementary Table S1).

Consistent with the NIH-CPSI, the severity of LUTS was ameliorated as measured by the IPSS. In comparison to the mean pre-ESWT IPSS of 13.9 ± 8.41, we recorded a 27.1%, 38.0%, 42.0%, and 50.9% time-dependent improvement, respectively, of urinary symptom severity at months 1, 2, 6, and 12 of ESWT (Figure 2C; Also see Supplementary Table S1).

Understanding that the severity of urinary symptoms, including pain, affects patients' QoL, we evaluated and demonstrated commensurate improvement in patients' QoL as per the AUA QOL\_US. The mean QoL score before ESWT was 4.29 ± 1.54. For the first, second, sixth, and twelfth months following ESWT, we recorded mean QoL values of 3.26 ± 1.93, 3.45 ± 2.34, 3.25 ± 1.69, and 2.6 ± 1.56, respectively (Figure 2D; also see Table S1).

A baseline-normalized paired sample mean of all evaluated parameters is shown in Table 1. Compared to pre-ESWT status, ESWT elicited statistically significant improvement in all patients' clinical parameters (*p* < 0.001), except for the EHS at 2 months (mean baselinepaired difference = 0.23, *p* = 0.096), 6 months (mean baseline-paired difference = 0.25, *p* = 0.351), and 12 months (mean baseline-paired difference = 0.10, *p* = 0.302) following ESWT, compared to the 40.9% mean improvement in EHS (*p* = 0.009) at 1 month following ESWT (Table 1).


**Table 1.** Comparison of paired samples parameters over

 time. QoL\_1 QoL\_pESWT\_12 a: Paired samples t-test; CPSI/NIH-CPSI = National Institute of Health Chronic Prostatitis Symptom Index; 95% CI = 955 confidence interval; SD = standard deviation; VAS = visualanalog scale; IPSS = International Prostate Symptom Score; QoL/AUA QoL\_US = American Urological Association Quality of Life Due to Urinary Symptoms; IIEF = International Index ofErectileFunction;EHS=erectilehardnessscore;ESWT=extracorporealshockwavetherapy;pESWT=post-extracorporealshockwavetherapy.

QoL\_pESWT\_6

QoL\_1

 14 56

4.25

±

1.59

 5.14

± 0.95

 3.21 2.61

±

1.57

−1.64

±

1.59

−2.07

to

−1.22

± 1.72

−1.93

± 1.33

−2.70 to

−1.16

 0.0001 <0.0001

**Figure 2.** Effect of extracorporeal shockwave therapy in patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPSS). Notched box-and-whiskers graphs showing the time-phased effect of extracorporeal shockwave therapy on the (**A**) erection hardness score, (**B**) international index of erectile function, (**C**) international pain symptom scale, and (**D**) American Urological Association Quality of Life due to Urinary Symptoms over a period of 12 months. \* *p* < 0.05, \*\* *p* < 0.01.

#### **4. Discussion**

In the past decades, several studies across different medical disciplines have indicated the therapeutic efficacy of ESWT to various degrees against diverse medial conditions, including spasticity after upper motor neuron injury [26], tendinopathies, musculoskeletal conditions and soft tissue disorders [27–32], refractory angina pectoris [33], erectile dysfunction [34], and sexual conditions other than erectile dysfunction [35,36]. While several studies have also suggested that the use of ESWT exerts a beneficial effect in patients with CP/CPPS [8,15–24], as with erectile dysfunction [37], the application of ESWT in the management of CP/CPPS is not without its controversies [23,25].

Although ESWT has been touted as a major therapeutic advance in the field of CP/CPPS in recent decades, as briefly summarized in Table 2, it remains far from being a perfect treatment paradigm and harbors certain limitations as already alluded to earlier [23–25].


**Table 2.** Review of previous studies on ESWT in patients with CP/CPPS.

22


*J. Clin. Med.* **2021**, *10*, 3602

**Table 2.** *Cont*.

23

Doppler flowmetry, (↓): statistical significance decrease (*<sup>p</sup>* < 0.05), (↑): statistical significance increase (*<sup>p</sup>* < 0.05), (−): no statistical difference (*<sup>p</sup>* > 0.05), NA: not available. Question mark (?)

implies lack of certainty, as the cited study itself lacked clarity on the association.

The present study demonstrated the beneficial effect of ESWT on pain, erectile function, and QoL in patients with CP/CPPS (*n* = 215) at our facility based on improved pain domain, urinary domain, QoL domain, and total score of NIH-CPSI, IIEF-5, EHS, IPSS, and AUA QoL\_US. Our findings are consistent with those of Yuan P. et al.'s meta-analysis, which demonstrated that low-intensity ESWT (Li-ESWT) was significantly efficacious in treating patients with CP/CPPS throughout the follow-up of 4 and 12 weeks, as well as at the 24 week endpoint, despite the statistically insignificant effect difference at 24-week follow-up due to insufficient data [38].

In our study, we demonstrated significant alleviation of pain in patients after ESWT. As mentioned by Zimmerman R et al. [24], the observed pain alleviation may be attributed to intracellular alterations following conversion of the mechanical extracorporeal shock-waves to biochemical signals. In addition to enhanced local microvascularization, coupled with reduced residual muscle tension and spasticity [24], we posit that the pulsatile stimulation of pain receptors (nociceptors) by ESWT disrupts in part or completely impedes the transmission of potential pain stimuli; it is also probable that ESWT simply overstimulates the nociceptors beyond their sensitivity threshold with consequent numbing of the sensory neurons to noxious stimuli, thus resulting in reduced pain perception. Concordant with the "neural pain memory" hypothesis put forward by Wess OJ [39], it is also conceivable that due to the plasticity of synapses, ESWT possibly effaces the noxious link established between pain sensory input and motor nerve signal output, and thereby reverses the sensation of chronic pain. Essentially, ESWT elicits the alleviation of pain by selectively eliminating pathological reflex patterns [24,39].

Furthermore, apart from pain alleviation, we also demonstrated that ESWT ameliorated the severity of other prostatitis symptoms in our CP/CPPS cohort with a 53.6% decrease in NIH-CPSI, 17.9% increase in IIEF-5, 6.8% increase in EHS, and 50.9% decrease in IPSS by month 12 after ESWT, concordant with the beneficial effect of ESWT in patients with CPPS (17% decrease in NIH-CPSI, 5.3% increase in IIEF, and 25% decrease in IPSS) reported by Zimmerman R et al. by month 3 after ESWT [24]. Additionally, this is consistent with the conclusions of a recent meta-analysis that "-ESWT showed great efficacy for the treatment of CP/CPPS at the endpoint and during the follow-up of 4 and 12 weeks" [38].

Moreover, because CP/CPPS-pathognomonic ED and LUTS significantly affect QoL, we demonstrated that ESWT improves the QoL of patients with CP/CPPS. This aligns with Zimmermann R et al.'s findings [24], and with reports that over 80% of patients that were non-responsive to therapy responded to ESWT by month 3, thus projecting ESWT as a salvage or rescue treatment for restoring clinical ability and improving QoL in patients with CP/CPPS who were refractory to the traditional 'three As' therapy [40]. In addition, Yan X, et al. [41] also documented significant improvement in all domains of the NIH-CPSI, including the QoL domain, and in the QoL as per the AUA QoL\_US.

A major strength of this study is that unlike most studies on the effect of ESWT on CP/CPPS, where the mean follow-up duration was 12 weeks (month 3) after ESWT, the present study followed patients up to 48 weeks (month 12) post-ESWT in order to rule out suggestions that the post-ESWT beneficial effects were transient or short-term. To the best of our knowledge, this is the longest documented follow-up duration for any study on the effect of ESWT in patients with CP/CPPS. Nevertheless, more studies exploring the long-term durability of ESWT efficacy and the safety profile across all standard clinical indices are warranted. Having said that, aside from one case of post-procedure dysesthesia, which was transient and mild, our results and observations indicate that ESWT is a safe treatment for CP/CPPS, as follow-up was uneventful, with no aggravated complications recorded through the entire 48 weeks of follow-up. None of the participants opted out of the study due to any reported treatment-related complication. Consistent with contemporary knowledge and documented reports, long-term complications of ESWT are unknown.

Like many studies of this nature, the present study has some limitations, including being a single-center study, thus prone to being critiqued for lack of external validation or the scientific rigor necessary for widespread generalization or consensus. Secondly, this was a prospective, single-arm cohort study, thus lacking a control or sham group for comparison and exclusion of placebo effect. Thirdly, the cohort size of 215 patients with CP/CPPS, though greater than the minimum necessary number (i.e., given an expected average improvement in CPSI total score of 5 points, the sample size required was 14 (α = 0.05, β = 0.8, σ = 6)) to meet the required statistical constraints, was relatively small and carried the risk of not representing CP/CPPS of all known pathoetiologies, thus necessitating the evaluation of the efficacy of ESWT in larger and multi-center cohort studies.

#### **5. Conclusions**

As summarized in our schematic abstract (Figure 3), the present study demonstrated that ESWT, an outpatient and easy-to-perform, minimally invasive procedure, effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with CP/CPPS. Our study highlighted the putative ability of ESWT to reverse the pathophysiology of CP/CPPS at the cellular level, elicit durable improvement in patients' clinical status, and restore spontaneous erectile function, with minimal or null side effects.

**Figure 3.** Schematic abstract: By disrupting pain stimuli transmission or overstimulation of nociceptors, ESWT effectively alleviates pain, improves erectile function, and ameliorates quality of life in patients with CP/CPPS through increased re-perfusion and numbing of sensory neurons to noxious stimuli, with associated reduction in residual muscle tension, spasticity, and pain perception.

> **Supplementary Materials:** The following are available online at https://www.mdpi.com/article/10 .3390/jcm10163602/s1, Table S1: Baseline and time-phased changes in NIH-CPSI, IIEF-5, EHS, IPSS and AUA QOL\_US Scores in participants (*n* = 215).

> **Author Contributions:** W.-L.W., O.A.B., C.-C.W.—Study conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing. Y.-H.W., S.-W.H., K.- Y.T., C.-T.Y.—Data analysis and interpretation. O.A.B., Y.-H.W., C.-C.W.—Provision of resources and administrative oversight. All authors have read and agreed to the published version of the manuscript.

**Funding:** This study received no external funding.

**Institutional Review Board Statement:** The study was approved by Taipei Medical University-Joint Institutional Review Board (Approval no.: N201712069), and written informed consent was obtained from all the enrolled patients. The study protocol was compliant with the Declaration of Helsinki.

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The data used and analyzed in the current study are available on request from the corresponding author.

**Acknowledgments:** The authors thank all attending physicians from the Department of Urology, Shuang Ho Hospital, Taipei Medical University, for their assistance with patients' data collation.

**Conflicts of Interest:** The authors declare that they have no conflict of interest.

#### **Abbreviations**


#### **References**


## *Article* **Comparison of Holmium:YAG and Thulium Fiber Lasers on the Risk of Laser Fiber Fracture**

**Audrey Uzan 1,2, Paul Chiron 1,2, Frédéric Panthier 1,2, Mattieu Haddad 1,2, Laurent Berthe 3, Olivier Traxer 1,2 and Steeve Doizi 1,2,\***


**Abstract:** Objectives: To compare the risk of laser fiber fracture between Ho:YAG laser and Thulium Fiber Laser (TFL) with different laser fiber diameters, laser settings, and fiber bending radii. METH-ODS: Lengths of 200, 272, and 365 μm single use fibers were used with a 30 W Ho:YAG laser and a 50 W Super Pulsed TFL. Laser fibers of 150 μm length were also tested with the TFL only. Five different increasingly smaller bend radii were tested: 1, 0.9, 0.75, 0.6, and 0.45 cm. A total of 13 different laser settings were tested for the Ho:YAG laser: six fragmentation settings with a short pulse duration, and seven dusting settings with a long pulse duration. A total of 33 different laser settings were tested for the TFL. Three laser settings were common two both lasers: 0.5 J × 12 Hz, 0.8 J × 8 Hz, 2 J × 3 Hz. The laser was activated for 5 min or until fiber fracture. Each measurement was performed ten times. Results: While fiber failures occurred with all fiber diameters with Ho:YAG laser, none were reported with TFL. Identified risk factors of fiber fracture with the Ho:YAG laser were short pulse and high energy for the 365 μm fibers (*p* = 0.041), but not for the 200 and 272 μm fibers (*p* = 1 and *p* = 0.43, respectively). High frequency was not a risk factor of fiber fracture. Fiber diameter also seemed to be a risk factor of fracture. The 200 μm fibers broke more frequently than the 272 and 365 μm ones (*p* = 0.039). There was a trend for a higher number of fractures with the 365 μm fibers compared to the 272 μm ones, these occurring at a larger bend radius, but this difference was not significant. Conclusion: TFL appears to be a safer laser regarding the risk of fiber fracture than Ho:YAG when used with fibers in a deflected position.

**Keywords:** Ho:YAG laser; thulium fiber laser; laser fiber; lithotripsy; urolithiasis; ureteroscopy

#### **1. Introduction**

Since its introduction in the 1990s, Ho:YAG laser has become the reference point for lasers for lithotripsy in urology because of its property to fragment all stone compositions, efficiencies and safety profiles [1–3]. Recently, a new laser has been released: the Super Pulsed Thulium Fiber Laser (TFL), with potential advantages over Ho:YAG laser such as higher ablation volumes during lithotripsy and production of thinner particles [4–8]. These two lasers use low hydroxyl silica optical fibers to transmit the laser beam to the stone [4,5,9,10]. During laser lithotripsy with flexible ureteroscopy (f-URS), laser fiber rupture may occur especially for lower pole stones treatment, resulting in working channel perforation and subsequent endoscope repair. Some studies reported risk factors of laser fiber fracture with Ho:YAG laser while bending: the diameter of the bend and high pulse energy [11,12]. While Ho:YAG laser and TFL are currently used for lithotripsy during f-URS, there is a lack of comparative study regarding the risk of laser fiber fracture during laser activation in a deflected position. Thus, we aimed to compare the risk of laser fiber

**Citation:** Uzan, A.; Chiron, P.; Panthier, F.; Haddad, M.; Berthe, L.; Traxer, O.; Doizi, S. Comparison of Holmium:YAG and Thulium Fiber Lasers on the Risk of Laser Fiber Fracture. *J. Clin. Med.* **2021**, *10*, 2960. https://doi.org/10.3390/jcm10132960

Academic Editor: Bhaskar K. Somani

Received: 10 May 2021 Accepted: 25 June 2021 Published: 30 June 2021

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

fracture between Ho:YAG laser and TFL with different laser fiber diameters, laser settings, and fiber bending radii.

#### **2. Materials and Methods**

#### *2.1. Laser Fibers*

Single use laser fibers of a unique manufacturer (Rocamed, Monaco) with core diameters of 200, 272, and 365 μm were used for both laser systems to avoid any confusion due to a variability in laser fibers characteristics. Additionally, 150 μm laser fibers were also tested with the TFL only.

#### *2.2. Laser Systems*

A 50 W Super Pulsed TFL generator (IPG Photonics, Fryazino, Russia) with a wavelength of 1940 nm was compared to a 30 W Ho:YAG laser (MH01-ROCA FTS-30W, Rocamed, Monaco) with a wavelength of 2120 nm. A total of 13 different laser settings were tested for the Ho:YAG laser: 6 fragmentation settings with a short pulse duration, and 7 dusting settings with a long pulse duration. A total of 33 different laser settings were tested for the TFL. Since TFL offers lower energies and higher frequencies than current Ho:YAG lasers, we aimed to evaluate these specificities. Three laser settings were common to both lasers: 0.5 J × 12 Hz, 0.8 J × 8 Hz, 2 J × 3 Hz. All laser settings tested are presented in Table 1.


**Table 1.** (**A**): TFL laser settings; (**B**): Ho:YAG laser settings.

#### *2.3. Experimental Setup*

The laser fibers were supported by soft silicone tubes, secured by plastic screws (to hold the fibers without causing damage). Failure threshold testing was done by bending fibers to 180◦ with an initial radius of 1 cm, Figure 1A,B. In total, five different increasingly smaller bend radii were tested: 1, 0.9, 0.75, 0.6, and 0.45 cm. The choice of the minimal bending radius (0.45 cm) was based on the fact that we measured the most acute angle over several cases that a flexible ureteroscope might deflect for lower pole lithotripsy in difficult anatomical situations. Subsequent radii were randomly chosen to test wider values mimicking calices easier to navigate through. The laser was activated continuously for 5 min or until fiber fracture. Each measurement was performed ten times.

**Figure 1.** (**A**) Fiber bending radius, (**B**) Fiber bending radii tested.

#### *2.4. Statistical Analyses*

The Mann–Whitney test was used for comparisons between groups. All tests were conducted using the R Software, version 4.0.3. A *p*-value of 0.05 or less was considered significant.

#### **3. Results**

We did not report mechanical failure by bending the fibers alone. All fractures occurred after laser energy application.

#### *3.1. Ho:YAG Laser*

#### 3.1.1. Dusting Settings

For the 200 μm fibers, the fracture rate was 50% at bending radius ≤0.6 cm, while none broke at radius ≥0.75 cm. For the 272 and 365 μm fiber diameters, fractures occurred only with a bending radius of 0.45 cm. A total of 20% of the 272 μm and 30% of the 365 μm fibers broke at a bend radius of 0.45 cm, Figure 2.

**Figure 2.** Proportion of fiber failures with Ho:YAG laser according to laser setting, fiber diameter, bending radius.

#### 3.1.2. Fragmentation Settings

Of the 200 and 272 μm fibers, there was no fracture for a bend radius ≥0.6 cm. While 90% of the 200 μm fibers broke at a radius of 0.45 cm, 50% of the 272 μm did. The 365 μm fibers broke more frequently at ≤0.75 cm. A total of 5% and 50% of 365 μm laser fibers broke with a bending radius of ≥0.75 and ≤0.6 cm, respectively, Figure 2.

#### 3.1.3. Identification of Risk Factors of Fiber Failure

Short pulse and high energy were significant risk factors of fiber fracture for the 365 μm fibers (*p* = 0.041), but not for the 200 and 272 μm fibers (*p* = 1 and *p* = 0.43, respectively). High frequency was not a risk factor of fiber fracture for all fiber core diameters.

Fiber diameter also seemed to be a risk factor of fracture. The 200 μm fibers broke more frequently than the 272 and 365 μm ones (*p* = 0.039). There was a trend for a higher number of fractures with the 365 μm fibers compared to the 272 μm ones, these occurring at a larger bend radius, but this difference was not significant.

#### *3.2. TFL*

Irrespective of the laser fiber diameter, laser settings, and bending radius, no fiber fracture occurred with the TFL.

#### *3.3. Ho:YAG versus TFL*

Irrespective of the laser settings, the fiber diameter and the bend radius, there was a significant risk of fiber fracture with the Ho:YAG laser compared to the TFL.

#### **4. Discussion**

The current study demonstrated a significant risk of fiber fracture with the Ho:YAG laser compared to the TFL in a deflected position. This result is of importance because nowadays f-URS has become a modality of choice for the treatment of kidney stones [13]. While Ho:YAG laser is currently the gold standard for lithotripsy during f-URS, TFL appears as an efficient alternative [14]. For both lasers, the laser energy is delivered to the target through a low hydroxyl silica fiber [9]. This laser fiber consists of a silica core through which the laser energy is transmitted. This core is surrounded by a layer called cladding that is essential for the efficient delivery of laser energy. This cladding is made of similar material to the core but has a different refractive index. Thus, the laser beam is reflected at the cladding–core interface. This process is called total internal reflection [9,10]. The most external part of the fiber is called jacket and encases the core and cladding. Its function is to protect the glass components of the fiber. When the fiber is bent, such as in lower pole stone treatment during f-URS, a small amount energy may leave the core to the cladding, and subsequently leak into the jacket. This condition represents a loss of total internal reflection of the laser energy, and once energy leaks into the jacket, fiber failure can occur due to thermal breakdown [15–17]. Prior studies demonstrated that the fibers do not fail with mechanical stress alone but rather fail when the laser is activated with the fiber in a deflected position. Consequences of such fiber failures are working channel perforations during laser activation, which represents an important cause of f-URS damage [18]. Several studies focused on the risk factors of fiber fracture in a deflected position with Ho:YAG laser [11,12,19–23]. They reported contradictory results regarding the influence of fiber diameter, bend radius, laser settings, and even for a same type of fiber from a specific manufacturer [12,20–22]. For example, while some authors reported that medium core fibers were prone to higher rates of failure than small core fibers, other studies did not document a correlation between increasing fiber diameter and fracture [11,20]. However, all the studies found that the resistance to fracture varies greatly among fiber manufacturers [12,20–22].

Similarly to Mues et al., we did not report mechanical failure by bending the fibers alone [21]. This means that failure is the consequence of loss of total internal reflection during laser activation in a bent fiber.

#### *4.1. Ho:YAG Laser*

The current study found that small core fibers (200 μm) were prone to a higher rate of fracture and failed at a larger bend radius (≤0.6 cm) than 272 and 365 μm fibers in dusting setting (0.45 cm only). Surprisingly, no 200 μm fiber failure occurred at a bend radius ≥0.6 cm in fragmentation setting, but there was a higher proportion of fractures than in dusting setting (90% versus 50%, respectively). Thus, we found that small core fibers failed significantly more often than the 272 and 365 μm ones. These results are consistent with the report by Mues et al., and may be explained by the beam profile of the Ho:YAG laser [21]. Indeed, the Ho:YAG laser beam does not couple small core fibers (<200 μm), and the risk may be overfilling the fiber core and leak laser energy to the fiber cladding, which can damage the fiber [4,5,24,25]. Thus, the use of small core fibers require the funneling of laser beam. As consequence, Ho:YAG laser is typically limited to larger fiber diameters (270–500 μm).

For the 272 and 365 μm fibers, we found similar results than Haddad et al., the 272 μm fibers failed at a smaller diameter than the 365 μm in fragmentation setting, but not in dusting setting.

Although 200 μm fibers are more flexible and may be more suitable for the treatment of lower pole stones during f-URS, they are more prone to failure when lasering. Thus, 272 μm core fibers seem a safer option for lower pole f-URS with Ho:YAG laser.

Finally, similarly to Knudsen et al., we found that the tightness of the fiber bend radius increases the risk of fiber failure as well as pulse energy for the 365 μm only [12]. This means that for a fixed bending radius, if the pulse energy increases, the amount of energy leaking the core to the cladding increases, and thus the risk of fiber fracture. On the contrary, Lusch et al. reported a trend for less fiber fracture at long pulse mode, high energy, low frequency in the small core fibers (200, 272/273 μm). Contrary to Vassar et al., we did not report an increase failure rate when the laser pulse energy increases with 272 μm fibers compared to the 365 μm [26].

#### *4.2. TFL*

Until now, no study has evaluated the risk of laser fiber fracture with the TFL. We found that, irrespective of the laser fiber diameter, laser settings, and bending radius, no fiber fracture occurred. These results may be explained by the beam profile and the peak power of the TFL. Contrary to the solid state Ho:YAG laser, the laser beam of the TFL originates within a small (18–25 μm) core of the thulium-doped silica optical fiber, which is about 100 times smaller in diameter than Ho:YAG laser. Furthermore, the TFL provides a near single mode Gaussian spatial beam profile, more uniform and symmetrical than the multimodal beam produced by the Ho:YAG laser [24]. Thus, even thinner laser fibers (150 μm) can be used with TFL. As consequence, total internal reflection may be respected in all fiber core diameters, with no leakage of energy through the cladding and jacket, which reduce the risk of fiber fracture. Moreover, peak power may also explain the absence of fracture with TFL. Indeed, the differences in fiber fracture rates between the two lasers systems may be explained by the constant higher peak power with the Ho:YAG laser compared to the TFL, regardless of the laser settings [27]. While peak power is directly correlated to the energy level with Ho:YAG laser and decreases with increased pulse duration, this remains constant with TFL. Furthermore, the pulse shape is also different with a flat and uniform shape for the TFL and a spike with an overshoot for the Ho:YAG laser [27]. Thus, the treatment of lower pole stone with TFL may be safer than with Ho:YAG laser, regardless of fiber diameter, bend radius, and laser settings.

Our study has several limitations, including the use of laser fibers from a unique manufacturer. However, by using exactly the same laser fiber manufacturer, it was possible to show the differences between both laser technologies, without risking the additional bias that using laser fibers from different origins might introduce. Yet, since great differences regarding size, flexibility, and resistance to fracture with bending among manufacturers exist, more optical fibers should be tested to ascertain our results with TFL. Although, laser fiber manufacturers provide short term minimum bending radius, we did not respect them in our tests since it is not possible to respect these minimal values in real conditions, especially in a difficult lower calyx access. Indeed, short term minimum bending radii were ≥13 mm, ≥17 mm, and ≥21 mm for the 200, 272, and 365 μm laser fibers tested, respectively. Another limitation was the absence of power transmission measurement. With transmission values, a quantitative correlation of core diameter, bending radius and losses might be possible. Lastly, laser activation duration was fixed at 5 min or until fiber fracture, which has resulted in different total energies delivered between powers tested. However, this might affect the results with Ho:YAG laser only, since no fiber fracture occurred with TFL.

#### **5. Conclusions**

The is the first study comparing the risk of fiber fracture with different laser fiber diameters, laser settings, and fiber bending radii between the Ho:YAG laser and TFL. While fiber failures occurred with all fiber diameters with Ho:YAG laser, none was reported with TFL. Further studies testing fibers from different manufacturers are needed to ascertain these results.

**Author Contributions:** Conceptualization, S.D.; data curation, S.D. and O.T.; formal analysis, S.D., P.C. and F.P.; investigation, S.D., P.C. and F.P.; methodology, S.D and F.P.; project administration, S.D.; resources, S.D.; validation, S.D.; writing—original draft, A.U.; S.D.; writing—review and editing, A.U., S.D., P.C. and F.P., M.H., L.B. and O.T. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data are available by contacting authors.

**Conflicts of Interest:** Olivier Traxer is a consultant for: Boston Scientific, Coloplast, EMS, IPG Medical, Olympus, Rocamed. Audrey Uzan, Paul Chiron, Frédéric Panthier, Mattieu Haddad, Laurent Berthe, and Steeve Doizi have no conflict of interest to declare.

#### **References**

