Sono-Electro-Magnetic Therapy for Treating Chronic Pelvic Pain Syndrome in Men: A Randomized, Placebo-Controlled, Double-Blind Trial

Objective To assess the efficacy and safety of sono-electro-magnetic therapy compared to placebo in men with refractory CPPS. Patients and Methods In a randomized, placebo-controlled, double-blind single center trial, we assessed the effect of sono-electro-magnetic therapy in men with treatment refractory CPPS. Sixty male patients were randomly assigned to treatment with either sono-electro-magnetic (n = 30) or placebo therapy (n = 30) for 12 weeks. The primary outcome was a change in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) from baseline to 12 weeks. Results The 12-week difference between sono-electro-magnetic and placebo therapy in changes of the NIH-CPSI total score was −3.1 points (95% CI −6.8 to 0.6, p = 0.11). In secondary comparisons of NIH-CPSI sub-scores, we found differences between groups most pronounced for the quality-of-life sub-score (difference at 12 weeks −1.6, 95% CI −2.8 to −0.4, p = 0.015). In stratified analyses, the benefit of sono-electro-magnetic therapy appeared more pronounced among patients who had a symptom duration of 12 months or less (difference in NIH-CPSI total score −8.3, 95% CI −14.5 to 2.6) than in patients with a longer symptom duration (−0.8, 95% CI −4.6 to 3.1; p for interaction = 0.023). Conclusions Sono-electro-magnetic therapy did not result in a significant improvement of symptoms in the overall cohort of treatment refractory CPPS patients compared to placebo treatment. Subgroup analysis indicates, however, that patients with a symptom-duration of 12 months or less may benefit from sono-electro-magnetic therapy, warranting larger randomized controlled trials in this subpopulation. Trial Registration ClinicalTrials.gov NCT00688506


Interventions
Meares-Stamey 3-glass test, uroflowmetry, measurement of post-void residual, measurement of PSA NIH-CPSI and pain diary Treatment with Sonodyn ® Medico Star therapy over a treatment period of 12-weeks (depending on the randomisation sono-electro-magnetic treatment or placebo treatment) MRI of the brain: before therapy and 12 weeks after therapy.

Study flowchart
Therapy with verum device Therapy and pain diary Therapy with placebo device Therapy and pain diary Background Chronic pelvic pain syndrome (CPPS) represents besides benign prostatic hyperplasia (BPH) and prostate cancer the third most common diagnosis in men with prostatic complaints under the age of 50 years 1. Approximately 8% of all urological outpatient consultations are due to CPPS [2]. Thus, CPPS is a serious economic burden on any health care system and quality of life is significantly impaired in affected individuals. The exact patho-mechanisms involved in CPPS are still unknown and many factors seem to contribute to this heterogeneous disorder [3]. Multimodal therapies are more successful than single therapies and a combination of antibiotics, alpha-blockers and/or nonsteroidal anti-inflammatory drugs seem to help some patients. However, approximately 30% to 50% of all patients find no relief in conventional therapies. Our Sonodyn ® Medico Star pilot study that treated patients using a combination of different kinds of neuromodulation reported encouraging findings: Sono-electro-magnetic therapy achieved an improvement in more than 40% of patients with treatment refractory CPPS after a treatment period of 6 and 12 weeks, respectively [4]. These results are promising especially considering the negative patient selection with various unsuccessful conventional therapies prior to sono-electro-magnetic treatment.
The mechanism of action of Sonodyn ® Medico Star treatment in men with refractory CPPS is largely unknown. However, a neuromodulative effect on different brain centers seems to be involved. A placebo-controlled trial setting is, in contrast to other neuro-modulative techniques, such as transcutaneous electric nerve stimulation (TENS) or sacral neuromodulation (SNM), possible with Sonodyn ® Medico Star as patients cannot perceive the device working because it uses subsensory stimulation.

Purpose
We hypothesize that combined sono-electro-magnetic therapy can improve refractory CPPS in men. In addition, we postulate that combined sono-electro-magnetic therapy as well as placebo therapy has a significant effect on brain activity detectable by functional MRI.

Hypothesis
Based on our pilot study we assume, that a 12-week treatment course with sono-electro-magnetic therapy will significantly improve symptoms in men with refractory CPPS compared to placebo treatment. Furthermore we assume a neuromodulative effect of the sono-electro-magnetic therapy on different brain centers.
Study end-points Primary outcome measures: National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) (time frame: before treatment, after 6 and 12 weeks of treatment as well as 4 weeks after stop of treatment) Treatment success is defined as an improvement of at least 4 points in the NIH-CPSI total score or a reduction in the NIH-CPSI pain score to a value < 8. Patients are instructed on how to perform sono-electro-magnetic therapy at home and to apply the device on the perineum daily in the morning and evening for the duration of ten minutes each time over the time period of 12 weeks. During the whole treatment period patients have to document for every single day in a diary whether they performed the treatment and they also have to conduct a pain diary. In addition, potential co-medication has to be documented in the dairy. MRI of the brain is performed before initiation of sono-electro-magnetic therapy.
After 6 and 12 weeks of therapy: Urinalysis and urine culture, uroflowmetry, post-void residual measurement and PSA measurement, NIH-CPSI.
After 12 weeks of therapy: MRI of the brain and stop of therapy 16 weeks after initiation of therapy: Urinalysis, uroflowmetry, measurement of post-void residual, measurement of PSA, NIH-CPSI Study end and unblinding: Patients with insufficient treatment response after placebo-therapy will receive a verum Sonodyn device by the manufacturer without additional cost for another 12 weeks of treatment. Patients with insufficient treatment response under verum therapy will be reassessed in the urological outpatient clinic and further treatment options will be considered, for instance physiotherapy.

Statistical analyses: sample size and power calculation
To detect a 4 point difference in the NIH-CPSI total score between baseline and after 12 weeks of therapy (assuming a standard deviation of 6.8, based on the data of the pilot study) at a two-sided significance level of 5% (α=0.05) with a power of 80% (β=0.20) a total of 50 patients has to be recruited (i.e. 25 patients in the verum and 25 patients in the placebo group, respectively). Considering a drop-out rate of 20%, a total of 62 patients should be included into the trial.

Risks and inconveniences
Up to now, there are no known risks or side effects by external application of Sonodyn ® Medico Star for treating muscle and joint complaints. In our pilot study in men with treatment refractory CPPS, there was 1 patient complaining about aggravation of symptoms under sono-electro-magnetic therapy and no other side effects were documented [4]. It is unclear, however, whether the symptom aggravation was really due to sonoelectro-magnetic therapy or whether it was just the spontaneous course of the disease. Patients with contraindications for MRI of the brain are excluded from the trial.
Sonodyn Corporation AG (Solothurn, Switzerland) will kindly provide all stimulation devices.