New Approaches to Nerve Stimulation Therapy for Bladder Pain Syndrome

Walter Reed National Military Medical Center

Status: Enrolling

Conditions: Bladder Pain Syndrome

Treatments: Procedure: Pulsed radiofrequency ablation; Procedure: Sham ablation

Study type: Interventional

Funder types: Other U.S. Federal agency

Identifiers

NCT06204874

WRNMMC-2023-0433

Details and patient eligibility

About

Many women suffer from bladder pain syndrome (BPS). There are many treatments, but there is no one universally effective option. The goal of this clinical trial is to explore the use of electrical energy directed towards a group of nerves, called the superior hypogastric plexus, for treatment of BPS in women over the age of 18 with a diagnosis of BPS. The main question it aims to answer is: does use of electrical micro-current directed at the superior hypogastric plexus improve pain associated with BPS over the use of placebo?

There is data from many different studies that suggest that this kind of therapy might provide relief of BPS symptoms.

Participants will be asked to participate for a total of six months from the date of their first nerve treatment. At the first appointment, they will be evaluated in the Walter Reed Chronic Pain clinic and asked several questions about the severity and personal management of their symptoms. The procedure will then be performed by inserting two needles into the back (one on either side of the spine) and directing extremely short bursts of electrical micro-current towards the target nerve. The medical term for this is "pulsed radiofrequency ablation." This procedure causes disruption on a microscopic level of nerve fibers that send pain sensations to the bladder and other organs in the pelvis. Some participants will receive treatment, whereas others will receive sham (placebo). Participants will not be informed of their treatment group until the conclusion of the study. Following this initial appointment, participants will be asked about their symptoms at 1-, 3-, and 6-month follow-up appointments. Participants will be asked about pain, mood symptoms, sexual function, and measures of bladder irritation. The procedure will only be performed once.

At the study conclusion, researchers will compare treatment and sham groups to see if pain scores, as well as other secondary outcomes listed above, are different between these groups.

Benefits of this study may include possible relief of BPS symptoms. This may help to advance research about treatments for BPS. This is a novel approach to the treatment of BPS and as such may provide benefits greater than those found in treatment outside of the study.

Full description

Interstitial cystitis / bladder pain syndrome (IC/BPS) is a complex chronic pain syndrome characterized by bladder pain, pressure, and discomfort with urinary urgency and frequency, without signs of infectious or alternative cause. It disproportionately affects women, with an estimated 3-7% prevalence among women in the United States, and with a prevalence of 61% among women with chronic pelvic pain. Pathophysiology is currently poorly understood and the cause is unknown. It is widely accepted that IC/BPS may be broken into Hunner-type and non-Hunner type variants; however, beyond this histopathologic distinction, there remains a wide variety of proposed inflammatory, structural, autoimmune, infectious, functional, and neurogenic contributors to the overall picture of disease.

Current treatment of IC/BPS in the United States is guided by recommendations from the American Urological Association (AUA) and the American Urogynecologic Society (AUGS). In 2022, the AUA released updated guidance for treatment of IC/BPS. They outline a graded approach to uncomplicated IC/BPS, including non-pharmacologic and behavioral treatments (diet, education, stress management, physical therapy), oral medications, intravesical instillations, or procedures such as cystoscopy with hydrodistension, onabotulinumtoxinA injections, or neuromodulation. Rather than presenting these therapies in a "step-up" fashion, the AUA notes that initial treatment type should depend on symptom severity and patient preference, and multiple simultaneous therapies may be considered. Surgery with cystectomy or bladder augmentation are considered last-resort therapies. Of note, many of these established treatment options may come with undesirable side effects, intolerable complications, risks associated with general anesthesia, or shorter-than-optimal duration of action.

Some authors note that there is no one consistently effective treatment for IC/BPS, and one estimate states that 10% of patients with IC/BPS are refractory to conservative, non-surgical treatments. There is also a substantial psychosocial burden of IC/BPS; most patients with the disease have seen numerous providers before being appropriately diagnosed, and have tried multiple therapies unsuccessfully. These patients frequently experience concomitant voiding and bowel dysfunction, sexual dysfunction, mood disorders, social isolation, and greater unemployment.

One important contributor to the constellation of findings in IC/BPS is a shift towards sympathetically-mediated pain sensation in the setting of chronic pain. Central sensitization is hypothesized to occur in IC/BPS as well as other chronic pelvic pain syndromes. Williams et al found that subjects with IC/BPS had diminished vagal activity and a shift towards sympathetic nervous system dominance as reflected by decreased high-frequency heart rate variability on tilt table testing. Charrua et al had similar findings, showing significantly lower mean variation of the standard deviation of the P wave interval (a marker of sympathetic overactivity) on tilt table testing as well as significantly higher twenty-four hour urinary noradrenaline in patients with IC/BPS. These studies implicate autonomic nervous system aberrancy as a key factor in IC/BPS. Neuromodulation is the intervention of choice for managing hyperalgesic autonomic nervous system dysfunction. While neuromodulation using implantable stimulators has been extensively studied in IC/BPS, little research has been done on chemical neurolysis, radiofrequency ablation, or other nerve interruption strategies for pain management in IC/BPS.

Superior hypogastric plexus block (SHPB) is an interventional strategy used in chronic pain management initially investigated for the management of chronic cancer-related pelvic pain. The procedure targets the superior hypogastric nerve plexus, which is a bilateral retroperitoneal structure at the approximate level of L5/S1. The structure provides innervation to pelvic viscera including the bladder, urethra, vagina, vulva, ovaries, uterus, and pelvic floor. A study conducted by Plancarte et al investigated the first use of SHPB for chronic pelvic pain related to cancer in 28 patients. By injecting aqueous phenol in the retroperitoneal space overlying the superior hypogastric plexus, their team demonstrated a mean pain reduction of 70% in those treated with the block, with 3 patients experiencing durable pain relief for over two years.

Since it was first described, the method has been studied extensively in the management of chronic pelvic pain, having been demonstrated to be safe and effective in several prospective, retrospective, and randomized-controlled trials. Rocha et al analyzed 180 patients across 10 years treated with the block in a retrospective cohort study; their findings supported those of Plancarte et al, with 50% pain reduction observed in 48.8% of patients at 6 month follow-ups with no major complications or procedure-related morbidity. Literature on the block is steadily growing, with numerous articles showing effective and safe use of the block in the conditions such as endometriosis, adenomyosis, post-cesarean section pain, and even in a case of pain associated with Mayer-Rokitansky-Kuster-Hauser syndrome. SHPB has also been explored for treatment of IC/BPS, though overall studies are lacking. A prospective unblinded randomized trial performed in Egypt found that superior hypogastric plexus chemical neurolysis was inferior to bladder hydrodistention in some markers of IC/BPS relief; however, of note, this study was not placebo-controlled and lacked statistical power.

Since its inception, the SHPB has gone through several iterations. One exciting forefront is the use of pulsed radiofrequency ablation (pRFA) in targeting the nerves of the superior hypogastric plexus. pRFA was first introduced in the mid-1990s, and since then has been used extensively in the treatment of pain conditions such as cervical radicular pain, trigeminal neuralgia, groin and perineal pain, myofascial pain, and complex regional pain syndrome. pRFA works by sending millisecond-duration bursts of current through an electrode tip inserted adjacent to a structure of interest. Its exact mechanism is unknown, but is hypothesized to involve local thermal effects, high-intensity electric fields at the electrode tip, lower electric field phenomena that potentiate long-term depression of neuronal transmission, modifications to morphology of mitochondria in target tissues, and disruption of microfilaments and microtubules. The evidence behind pRFA is promising, and its safety is extremely well established, however, there is a striking paucity of prospective randomized controlled trials assessing its efficacy. Our literature review uncovered only one article investigating the use of pRFA of the superior hypogastric plexus for treatment of IC/BPS - a case report in which the patient experienced durable symptom relief for over two years. In their conclusion, the authors of this case report note that prospective randomized controlled study is warranted to confirm the clinical efficacy and safety of this procedure for the treatment of interstitial cystitis.

Given the factors outlined above - namely, (1) the predominance of central sensitization and sympathetic overactivation in IC/BPS, (2) the efficacy and anatomic relevance of SHPB in multiple pelvic pain syndromes, and (3) the established neuromodulatory utility of pRFA - it is reasonable to consider that pRFA of the superior hypogastric plexus may be an efficacious therapy for treatment of IC/BPS. Therefore, the primary aim of this study is to assess the efficacy of pRFA of the superior hypogastric plexus, as compared to treatment with sham, in patients with IC/BPS. The primary outcome will be post-intervention VAS pain scores at 1, 3, and 6 month follow-ups. Secondary outcomes will include ratings of urinary manifestations, measures of mood symptoms, measures of sexual function, and overall patient satisfaction in both treatment and sham groups.

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Citations:

Available on request.

Enrollment: 38 estimated patients

Sex: Female

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Female sex
• Age greater than or equal to 18
• Diagnosis of Bladder Pain Syndrome as evidenced by score greater than or equal to six on O'Leary-Sant Voiding and Pain Indices
• DEERS-eligible health care beneficiaries

Exclusion criteria

• Patients with current enabled implantable neurostimulation (i.e. transcutaneous electrical nerve stimulation unit, Interstim)
• Current active pelvic or gynecologic malignancy
• Coagulation disorder
• Local infection at injection site
• Sepsis
• Decompensated cardiac or hemodynamic disorders
• Neurogenic bladder and patients with spinal cord injury
• Current pregnancy
• Structural abnormalities of the spine that prevent performance of the procedure
• Intravesical onabotulinumtoxin A injection within the last 3 months

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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38 participants in 2 patient groups

Pulsed Radiofrequency Ablation Arm

Experimental group

Description:

18 total subjects in this arm. Subjects will be laid in the prone position. Local anesthesia will be administered. The appropriate spinal interspace will be identified under fluoroscopic guidance and hollow-tip needles will be inserted through the back into the retroperitoneal space adjacent to the superior hypogastric plexus. A microelectrode will be inserted through the hollow needle. A test pulse will be delivered. When proper positioning has been confirmed, 4mL of 1% lidocaine without epinephrine will be administered to reduce discomfort associated with radiofrequency ablation. Pulsed radiofrequency ablation will be performed at a pulse frequency of 2Hz, pulse width of 20ms, temperature of 42 degrees Celsius, total duration 120 seconds. The microelectrode and hollow-tip needle will then be withdrawn.

Treatment:

Procedure: Pulsed radiofrequency ablation

Sham Arm

Sham Comparator group

Description:

18 total subjects in this arm. Subjects will be laid in the prone position. Local anesthesia will be administered. The appropriate spinal interspace will be identified under fluoroscopic guidance and hollow-tip needles will be inserted through the back into the retroperitoneal space adjacent to the superior hypogastric plexus. A microelectrode will be inserted through the hollow needle. A test pulse will be delivered. Sham pulsed radiofrequency ablation will then be performed with the radiofrequency generator disconnected from the microelectrode. The duration of the sham procedure will be 120 seconds. The microelectrode and hollow-tip needle will then be withdrawn.

Treatment:

Procedure: Sham ablation