Use of Adjuvant Rectal Diazepam with Oral Tadalafil for Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

doi:10.21203/rs.3.rs-2814770/v1

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Use of Adjuvant Rectal Diazepam with Oral Tadalafil for Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

https://doi.org/10.21203/rs.3.rs-2814770/v1

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Studies show oral Tadalafil and Diazepam suppositories each independently improve chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), leading providers to use medications simultaneously in the same patients. Our objective was to explore the efficacy of Tadalafil in CP/CPPS symptom management and whether co-administration of rectal Diazepam enhances potential benefit. A single-institution, retrospective chart review was performed on 63 adult males with CP/CPPS. NIH-Chronic Prostatitis Symptom Index (CPSI) questionnaires were collected before and after at least 45 days of treatment with either Tadalafil alone (n = 40) or Tadalafil with adjunctive Diazepam suppositories (n = 23). Both groups had similar baseline pain and urinary CPSI sub-scores, yet patients treated with Diazepam had significantly worse median quality of life sub-scores on both the initial (8.5 vs. 11, P = 0.01) and final (4 vs. 8.5 P = 0.02) surveys. For both groups, CPSI aggregated scores and pain, urinary, and quality of life sub-scores were significantly reduced compared to scores before treatment (P < 0.0001-0.02). However, the reduction in symptom scores was not significantly different with the addition of Diazepam suppositories (P = 0.47–0.94). Tadalafil, both with and without Diazepam, improved CP/CPPS symptom scores across all domains of the CPSI questionnaire. However, Diazepam suppositories do not confer additional benefit compared to Tadalafil therapy alone for CP/CPPS.

Health sciences/Health care/Therapeutics

Health sciences/Health care/Quality of life

chronic prostatitis with chronic pelvic pain syndrome

inflammation

pelvic floor disease

pelvic pain

tadalafil

diazepam

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a debilitating and poorly characterized condition. It is the third most common genitourinary diagnosis amongst male patients, behind only benign prostatic hypertrophy (BPH) and prostate cancer (1). CP/CPPS is also the most common reason why men under 50 years old consult a urologist (2). Patients experiencing CP/CPPS often report urogenital pain affecting the testicles, penis, and rectum; sexual dysfunction; and obstructive or irritative lower urinary tract symptoms (LUTS)(1). CP/CPPS severity correlates with negative quality of life metrics and higher healthcare expenditures (1).

Despite CP/CPPS’ profound effects and prevalence, the medical and scientific community knows little about its underlying pathophysiology. Multiple systems and etiologies – such as neurologic, endocrinologic, psychologic, and infectious – likely contribute to the onset and perpetuation of the disease. Hence, the approach to CP/CPPS treatment remains multimodal – including antibiotics, alpha-blockers, anti-inflammatories, and 5-alpha reductase inhibitors (3). Other non-pharmacologic therapies include pelvic floor physical therapy, acupuncture, dietary modification, thermotherapy, and psychological support (1). Despite a robust body of literature exploring new and existing treatments for CP/CPPS, no regimen consistently reduces symptom burden across all groups of men (1,4–6).

Phosphodiesterase inhibitors (PDEi) have demonstrated potential therapeutic effects for CP/CPPS by alleviating the excessive prostatic and bladder muscle tension observed in this disease state (4,7). Intravaginal Diazepam suppositories - through their antispasmodic activity - modestly improve sexual dysfunction in female patients when used as adjunctive treatment for high-tone pelvic floor dysfunction (8). However, the utility of such an adjunctive treatment in male patients with CP/CPPS remains unknown. Our study aimed to explore the ability of the phosphodiesterase inhibitor Tadalafil to alleviate CP/CPPS symptom burden and determine if co-administration of Diazepam, a benzodiazepine, with a PDE5i enhances the potential therapeutic benefit in CP/CPPS patients.

Study sample

We performed a retrospective chart review to obtain data on adult males with CP/CPPS treated with a minimum daily dosage of 2.5 mg Tadalafil with or without Diazepam suppositories by a single urologist at a large-volume, tertiary academic medical center between September 2017 and May 2022. All patients prescribed Tadalafil monotherapy were offered a concurrent prescription for adjunctive rectal Diazepam suppositories which can be filled and used if the patient feels their symptoms are severe or poorly controlled. Our institutional review board acknowledged this study as exempt research (IRB00199004). Exclusion criteria included the absence of Tadalafil prescription, Tadalafil prescribed for conditions other than CP/CPPS (erectile dysfunction, positive urine cultures, neuropathic pain, etc.), patient-reported nonadherence to Tadalafil regimen, fewer than 45 days of treatment, incomplete records, or lost to follow-up.

Initial queries of ICD-10 diagnoses codes for encounters including “chronic prostatitis” and “pelvic and perineal pain” yielded 188 patients. After review of patient records, 125 patients were omitted based on exclusion criteria (Fig. 1). A total of 63 patients were included in the study. These patients were classified into a Tadalafil-only group (n=40) and a Tadalafil with adjunctive 5 or 10 mg Diazepam suppositories group (n=23).

Data collection and symptom scoring

Background information – such as demographics and past medical history – was collected for all patients. Demographic data obtained included age and race. Past medical history obtained included: hypertension, diabetes, cerebrovascular accident, myocardial infarction, chronic kidney disease, chronic obstructive pulmonary disease, anxiety, depression, fibromyalgia, lower back pain, and irritable bowel syndrome. Treatment regimens documented for analysis included prior or concurrent use of alpha-1 antagonists, use of steroids and other anti-inflammatory drugs, attendance at pelvic floor physical therapy (PFPT), and other non-pharmacological treatments (i.e., quercetin).

LUTS and quality of life scores were measured using the NIH-Chronic Prostatitis Symptom Index (CPSI). The CPSI is a validated instrument used to evaluate CP/CPPS that assesses three domains: pain, urinary symptoms, and the impact on quality of life (QoL)(9,10). CPSI questionnaires were collected before and after at least 45 days of treatment with Tadalafil regardless of Diazepam use. In instances where no baseline CPSI score existed in the electronic health record, CPSI scores were calculated based on symptoms and narrative comments documented in the encounter note closest to the treatment initiation. In two patients, the independent “quality of life” question of the CPSI was unavailable. These patients were omitted for analysis for this question alone and aggregate scores that used this item.

Statistical analysis

Results were analyzed using Microsoft Excel (Redmond, WA) and Stata (College Station, TX) with significance set at α=0.05. Demographic characteristics, past medical history, and CPSI scores were compared within and between treatment groups using non-parametric hypothesis tests, including Mann-Whitney U, Fisher’s Exact, and Wilcoxon signed-rank. Univariate logistic regression analyses were conducted to determine if CPSI scores before or after treatment were predictive of patients adhering to the combination regimen.

Overview

Sixty-three male patients with a median age of 42 (interquartile range: 33, 54) were included in the sample. Twenty-three percent of the patients identified as non-white and racial composition did not significantly differ between the groups (Table 1). Forty patients were treated with oral Tadalafil alone and 23 were treated with both oral Tadalafil and Diazepam suppositories. The duration of therapy between the baseline CPSI evaluation and the follow-up questionnaire ranged from 48 to 1,552 days with a median of 182 days (IQR: 91, 382). The duration of therapy did not significantly differ between groups (Table 1).

Notably, 56.5% (13/23) of patients treated with Diazepam were previously prescribed Baclofen for CPPS, whereas none of the patients prescribed Tadalafil alone were treated with Baclofen. Additionally, rates of clinical anxiety and the use of pelvic floor physical therapy were significantly higher in the group that used both treatments (P = 0.018 and P = 0.011, respectively). All other medical comorbidities, prior failed treatments, and concurrent therapies were similar between groups (Table 1).

Reductions in symptom scores irrespective of Diazepam use

Both groups had similar baseline pain and urinary CPSI sub-scores. Patients treated with adjunctive Diazepam had significantly worse quality of life sub-scores on both the initial and final surveys (P = 0.01 and P = 0.02, respectively. Table 2). Univariate logistic regression analysis revealed that the severity of quality of life sub-scores following treatment was predictive of patients pursuing, and adhering to, adjunct Diazepam suppositories (β = 0.19; P = 0.016; 95% CI [0.03–0.35]). Before or after therapy, no other CPSI scoring domains were predictive of Diazepam use (Table 3). For both groups, the final aggregate CPSI scores (P < 0.0001 and P < 0.0001) were significantly reduced compared to pre-treatment baselines (Fig. 2). Pain (P < 0.0001 and P < 0.0001), urinary (P = 0.007 and P = 0.013), and quality of life (P < 0.0001 and P = 0.0002) sub-scores were also all significantly reduced compared to their pre-treatment baselines (Fig. 2). However, the degree of the reduction in symptom scoring did not significantly differ between groups (P = 0.47–0.94, Fig. 3).

Key findings

This study evaluated the efficacy of Tadalafil therapy on CP/CPPS symptom burden and assessed whether concurrent treatment with Diazepam suppositories enhanced the potential benefits of Tadalafil alone. To our knowledge, this is the first and only study comparing the effects of PDE5i with Diazepam relative to PDE5i alone in use for CP/CPPS patients.

Our finding of global CP/CPPS symptom improvement with Tadalafil therapy relative to initial symptoms is consistent with previous literature (1, 4). Significant improvements across all domains of the CPSI survey (pain symptoms, urinary symptoms, and quality of life) were observed for male patients taking Tadalafil regardless of Diazepam suppository use. Total scores for both groups decreased by more than four points, which is the questionnaire’s presumed minimal clinically significant difference (11, 12). Our findings, however, failed to show significantly greater symptom alleviation among patients receiving adjuvant Diazepam. This finding applies to the total CPSI score and any of the sub-scores in the pain, urinary, or quality of life domains.

In our study, patients who opted to supplement their treatment with adjunctive Diazepam suppositories were more likely to have attempted pelvic floor physical therapy and to be prescribed Baclofen. Diazepam suppositories were pursued as a more aggressive treatment option compared to Tadalafil alone, and the addition of Diazepam, a potentially addictive benzodiazepine, was reserved for patients who were not satisfied with conservative management through monotherapy. Additionally, patients in the Diazepam group had higher rates of anxiety and worse quality of life sub-scores on both the initial and final CPSI questionnaires relative to the Tadalafil monotherapy group. Baseline total CPSI scores, however, were similar between groups. As previously described, the management of CP/CPPS is believed to be influenced some psychiatric etiologies. Consequently, those who opted to pursue the more aggressive combination therapy treatment may have in part done so due to concurrent psychological stress that exacerbated their disease.

Review of pathophysiology and mechanisms of action

Excessive prostatic and bladder muscle tension is the putative mechanism behind many of the LUTS experienced by those suffering from CP/CPPS (7). Many believe PDEis, such as Tadalafil, alleviate CP/CPPS symptoms by facilitating smooth muscle relaxation through modulation of the nitric oxide pathway (7). This smooth muscle relaxation may also improve urinary tract blood perfusion and prevent or reverse ischemic changes that also contribute to CP/CPPS severity (13, 14).

Benzodiazepines, such as Diazepam, reduce neuronal excitability through binding to benzodiazepine receptors (BZ-R) in the central nervous system. This mechanism enhances binding of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) to its receptors (15). We hypothesized that the resulting local myorelaxant effect of benzodiazepines could alleviate the ischemic changes seen in CP/CPPS (5). Past research on Diazepam vaginal suppositories in female patients with pelvic floor dysfunction has produced mixed results (6). Though a retrospective study found that intravaginal Diazepam improved symptoms (8), two double-blind, randomized, placebo-controlled trials failed to confirm these findings (16, 17). Our study, which assessed male patients, showed that patients did not receive additional benefit from Diazepam suppositories. This suggests that Diazepam did not significantly improve ischemic changes in the prostate or bladder beyond the improvement achieved with Tadalafil alone.

Limitations and future directions

This study has several limitations. All patients were seen by the same provider at a single institution, raising the possibility of selection bias. Our study was retrospective and thus prevented either patient or provider blinding. Nineteen patients were lost to follow-up. This raises a possibility of non-response bias since excluding these patients may have prevented the inclusion of patients who experienced enough benefit from these medications to not seek further medical care. The absence of any observed difference in CPSI score changes between the Tadalafil and Tadalafil with Diazepam groups may also be the result of low statistical power rather than an actual lack of difference. Future work should involve larger numbers of patients recruited from multiple institutions to confirm our findings. Finally, this study did not assess objective, functional outcomes resulting from Tadalafil and/or Diazepam use, such as post-void residual urine volume, prostate volume, or prostate blood flow.

Our study suggests that the addition of Diazepam suppositories to the therapeutic regimen for CP/CPPS does not confer additional benefit relative to Tadalafil monotherapy. Patients who received Tadalafil - both with and without adjuvant Diazepam - displayed significant improvements in CP/CPPS symptoms according to the CPSI questionnaire. Larger, multi-institutional studies are needed to confirm these findings.

Author Contributions

E Pil: Data collection and management, Data analysis, Manuscript writing/editing

O Li: Data collection and management, Manuscript writing/editing

N Engel: Data collection and management, Manuscript writing/editing

MJ Rabinowitz: Data collection and management, Data analysis, Manuscript writing/editing

VN Peña: Data collection

AS Herati: Protocol/project development, Manuscript writing/editing

Data Availability Statement

The dataset generated and analyzed during the current study are available from the corresponding author on reasonable request.

Funding: No financial assistance was received in support of the study.

Ethical Approval: The Institutional Review Board (IRB) of the Johns Hopkins University School of Medicine approved this study (IRB00199004) and written consent was waived due to retrospective nature.

Conflict of Interest: The authors have no financial or competing interests to declare that are relevant to the content of this article.

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Table 1 to 3 are available in the Supplementary Files section.

There is NO conflict of interest to disclose.

Table1.xlsx
Table 1. Past medical history, concurrent therapies, and duration of treatments. P-values represent differences between Tadalafil and Tadalafil + Diazepam groups. Medians reported with interquartile ranges and percentages reported with count/total.
Table2.xlsx
Table 2. CPSI aggregate scores and sub-scores. P-values represent differences between Tadalafil and Tadalafil and Diazepam groups.
Table3.xlsx
Table 3. Univariable logistic regression analyses reporting the predictive value of CPSI sub-scores and aggregate scores for rectal Diazepam use (≥45 days) among all patients receiving oral Tadalafil therapy (N=63). CI= Confidence Interval.

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Use of Adjuvant Rectal Diazepam with Oral Tadalafil for Treatment of Chronic Prostatitis/Chronic Pelvic Pain Syndrome

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Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Overview

Reductions in symptom scores irrespective of Diazepam use

Discussion

Key findings

Review of pathophysiology and mechanisms of action

Limitations and future directions

Conclusions

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1