IC PaIN Trial: Interstitial Cystitis Pain Improvement With Naltrexone

Study Overview
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Brief Summary
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Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating condition with symptoms of urinary urgency, frequency, nocturia (waking up at night to void), and pain, without evidence of urinary tract infection or other identifiable causes. IC/PBS often coexists with other chronic pain syndromes, such as irritable bowel syndrome, chronic fatigue syndrome, and fibromyalgia. Several treatments exist for IC/PBS; some are not effective, others are time consuming for patients to receive, some can take weeks to months before they become effective, and many have risks associated with them. Low-dose naltrexone (LDN) has demonstrated improvement of symptoms in conditions associated with IC/PBS. LDN is defined as less than 5mg of naltrexone. Some adverse effects have been reported with LDN, the most common are vivid dreams, nightmares, and insomnia. The investigators hypothesis LDN will have greater than 30% reduction in symptoms as defined by the Interstitial Cystitis Symptom Index in patients diagnosed with IC/PBS from baseline when compared to placebo. The 30% reduction in pain is a standard outcome measure in the pain literature. This improvement has been seen in prior studies where LDN was used to treat pain syndromes. This will be a randomized double-blinded placebo-controlled prospective trial. Patients meeting diagnostic criteria for IC/PBS by American Urologic Association (AUA) guidelines will be eligible, and then must then meet all applicable inclusion and exclusion criteria. Study participants will sign a consent, complete several questionnaires, give a blood sample to measure liver function tests, and once at home, complete a 24-hour bladder diary. Participants will be randomized to receive either placebo or study medication. Participants will be instructed to take one capsule nightly for two weeks, then increase to two capsules nightly for four weeks. They will be given a log to record the date and time they take the medication. All study participants will also receive first-line behavioral therapy for IC/PBS of a bladder diet and bladder drills. After six weeks, participants will complete a second bladder diary. They will then complete the exit study questionnaires, have a second liver function test, return any unused medication, and meet with their doctor to discuss conventional treatment options for IC/PBS.

Official Title
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IC PaIN Trial: Interstitial Cystitis Pain Improvement With Naltrexone, the Effect of Low Dose Naltrexone on Symptoms and Pain of Patients With Interstitial Cystitis/Painful Bladder Syndrome a Randomized Placebo-controlled Prospective Trial

Conditions
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Interstitial Cystitis, Painful Bladder Syndrome, Bladder Pain Syndrome, Low Dose Naltrexone, Low-dose Naltrexone, Naltrexone

Intervention / Treatment
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* Drug: low-dose naltrexone
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged eighteen and older Meet criteria for IC/PBS as defined by the American Urology Association as an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the urinary bladder, associated with lower urinary tract symptoms or more than six weeks duration, in the absence of infection or other identifiable causes (8) Newly diagnosed and treatment naïve for IC/PBS or previously diagnosed with IC/PBS, but who have no received treatment in the past four weeks. Patient who use anti-inflammatory medication on an as needed basis in the four weeks prior to the study will be included. Have had a cystoscopy in the last 6 months prior to study entry to rule out confounding conditions English speaking Working telephone number Able to provide a blood sample to evaluate liver enzymes Able to attend research visits Exclusion Criteria: Patients under the age of 18 Patients with known liver disease, including total bilirubin >1.2, AST> 32, ALT> 54 Patients with known kidney disease Patients who have thyroid disease and who are taking thyroid replacement medications Patients with known neurologic disease affecting bladder function Patients with known bladder or urethral cancer Patients with bladder, urethral, or ureteral calculi Patients who have had a positive urine culture or a clinical UTI in the past 6 weeks Patients who are currently pregnant or breast feeding (15) Patients who are actively using opioid analgesics Patients with moderate-severe alcohol use disorder Patients who are actively using sleep aids Patients who are regularly using anti-inflammatory medications, such as daily Celebrex for arthritis. Those who use an anti-inflammatory medication on an as needed basis may use the medication prior to enrollment in the study. Patients who have had a known adverse reaction to naltrexone Patients who are acutely ill Patients who are diagnosed with a significant psychological comorbidity that would interfere with study participation (32) Patients who have had a bladder instillation or had oral medical treatment for IC/PBS in the past four weeks. Patients diagnosed with other chronic pelvic pain syndromes, such as endometriosis Patients who are unable to swallow pills/capsules Patients who have had previous treatment with low-dose naltrexone Patients who have previously scheduled surgeries or procedure during the study time period that would require analgesia. Patients who are sexually active and of childbearing potential who are unwilling to use an established and reliable form of contraception for the duration of the study. Patients who are unwilling to have a serum blood test to assess serum transaminases and serum bilirubin.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 110 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low-dose naltrexone<br>2mg low-dose naltrexone capsules | Drug: low-dose naltrexone<br>* 2mg of low-dose naltrexone nightly for 2 weeks, then 4mg of low-dose naltrexone nightly for 4 weeks<br>|
| Placebo Comparator: Placebo<br>Placebo capsules | Drug: Placebo oral tablet<br>* 1 capsule nighty for 2 weeks, then 2 capsules nightly for 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interstitial Cystitis Symptom Index | The effect of LDN in decreasing symptoms associated with IC/PBS when treating with low-dose naltrexone as scored by the Interstitial Cystitis Symptom Index as compared to placebo. Scores are from 0 to 20, with lower scores indicating less symptoms associated with IC/PBS. | six weeks | 
| Visual analog scale | The effect of LDN in decreasing pain associated with IC/PBS when treating with low-dose naltrexone as scored by visual analog scale as compared with placebo. Scores are from 0 to 100, with lower scores indicating less pain. | six weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Interstitial Cystitis Problem Index | The decrease in IC/PBS associated problems when treating interstitial cystitis/painful bladder syndrome with low-dose naltrexone as scored by the Interstitial Cystitis Problem Index. Scores are from 0-16, with lower scores indicating a better score, with fewer problems associated with IC/PBS. | six weeks | 
| Urinary frequency | The change in number of patient voids during the day when comparing LDN against placebo as determined from 24 hour bladder diary performed by patient prior to initiating treatment, and at the conclusion of 6 weeks of treatment. | six weeks | 
| Nocturia | The change in number of patient voids during at night when comparing LDN against placebo as determined from 24 hour bladder diary performed by patient prior to initiating treatment, and at the conclusion of 6 weeks of treatment. | six weeks | 
| pelvic pain and urgency/frequency symptoms | The change in pelvic pain and urgency/frequency symptoms as measured on the Pelvic Pain and Urgency/Frequency Patient Symptom Scale. Scores can range from 0-23, with higher scores indicating more severe symptoms associated with IC/PBS. | six weeks | 
| pelvic pain and urgency/frequency bother | The change in pelvic pain and urgency/frequency bother as measured on the Pelvic Pain and Urgency/Frequency Patient Symptom Scale. Scores can range from 0-12, with higher values corresponding to more bother from IC/PBS symptoms. | six weeks | 
| Patient perceived changes in quality of life: SF-36 | Patient perceived changes in quality of life as measured by the medical outcomes study short form 36 (SF-36). Higher scores indicate a more favorable health status. There are 8 subscales, which when averaged, include a score from 0-100. | six weeks | 
| Adverse effects | The percentage of patients complaining of adverse effects from LDN including vivid dreams, nightmares, insomnia, GI disturbances such as stomach cramps or diarrhea, agitation, anxiety, flu-like symptoms and headaches. | 6 weeks | 
| Medication tolerability | Patient tolerability of low-dose naltrexone using a tolerability survey, as well as instructing the patient to return any remaining medication at the end of the 6 week study period | 6 weeks | 
| Change in pain medications | The decrease in use of pain medications while using LDN as determined by a pain medication diary | 6 weeks |