Hypothesis / aims of study
In animal models of OAB, typically silent C fibres become spontaneously active and hypersensitive to low-intensity input (1). Irradiation with low-level light (NIRL – near-infrared laser light) reduces immediate neuronal excitability (2). We postulate that photobiomodulation using NIRL may stabilise the autonomic regulation of the descending neural pathways from the Pontine Micturition Centre to the urinary bladder in OAB patients.
This study aimed to i) establish the safety of NIRL delivered via a nasal prong in patients with OAB symptoms undergoing UDI, ii) quantify the immediate effect of NIRL on detrusor pressure and filling volume during the urodynamic investigation (UDI), and iii) evaluate the efficacy of multiple-dose NIRL as a treatment for reducing OAB symptoms' severity.
Study design, materials and methods
Two-step methodology approved by the institution Human Research Ethics Committee: 1) a repeated measures proof-of-concept observational study of safety profile (primary endpoint) and immediate effect of NIRL on UDI measures (secondary endpoint) in 10 participants with proven DO. 2) single-case experimental design to enable testing of the safety and efficacy of a novel intervention in a small group of OAB patients (n=3-6) using a non-concurrent, multiple baselines, repeated measure across-subjects format.
Potential participants were ineligible if they were pregnant, demonstrated bladder outlet obstruction or moderate to severe voiding dysfunction, evidenced high/untreated blood pressure, were cognitively impaired, or had serious medical conditions. Inability to communicate in English or to wear the nasal prong that was used in this study were exclusion criteria.
Study 1: Before UDI, conditional consent was obtained for a second fill if DO was identified. NIRL was subsequently applied in eligible patients for the duration of the second UDI. Data collected: max detrusor pressure, volume at first involuntary detrusor contraction; volume at strong desire to void; maximum volume; blood pressure at the beginning and end of the second UD fill; any events that occurred during the 2nd UDI; 3-day bladder diary variables, OAB Symptom Score (OABSS) and Overactive Bladder Health Related Quality of Life Questionnaire (OAB-q part A).
Study 2: Informed consent was obtained from non-treatment naïve individuals presenting to the clinical service with urinary urgency with or without urgency incontinence. Data obtained: demographic information; clinical history relevant to OAB; blood pressure measures in sitting; OABSS and OAB-q part A. Four-week phases: 1) Baseline with twice-weekly measures of urinary frequency and OSABSS. 2) Intervention of 10 Hz delivered via a single-patient transparent polycarbonate intranasal diode for 25 minutes daily; urinary frequency and OABSS completed twice each week; side effect documentation and weekly blood pressure measures; OAB-q after four weeks. 3) Follow-up with no treatment; OABSS and urinary frequency measures twice weekly; ICIQ-OABqol after four weeks.
The analysis for study 1 utilised descriptive statistics. Given the small sample size, median differences in the four endpoints of interest pre and post-NIRL were calculated using the Wilcoxon Signed Rank Test and 95% confidence intervals presented. A two-sided alpha significance level of 0.05 indicated statistical significance.
Study 2 analysis: Within-phase level was reported as the mean or median of the phase data points; the trend was determined by assessing whether the data points were monotonically increasing or decreasing; stability of the data was evaluated by calculating the percentage of data points within 15% of the phase mean (or median) with stability satisfied at 80%. Between-phase examination utilised the Tau-U statistic to quantify the proportion of measurements in the intervention phase not overlapping with the baseline measurements. Tau-U score computations were obtained using the Tau-U Calculator (Single Case ResearchTM USA). Due to variation in OABSS in all participants, all statistics were corrected for the baseline trends.
1) NIRL was applied for the duration of the 2nd UDI in 10 participants (mean age 60 years, 60% female). No statistically or clinically significant changes in systolic or diastolic blood pressure occurred during the 2nd UDI (8-20 minutes) with NIRL in situ. Nil adverse events were reported. No statistically significant differences were identified for any secondary endpoint during the 2nd UDI fill, although median bladder volume at normal desire to void during the 2nd UDI (235mL) trended towards being higher than the median (185mL) bladder volume at normal desire to void during the 1st urodynamic fill (p=0.102).
2) Four participants with unremitting OAB completed the baseline, intervention, and follow-up phases of the trial. Visual inspection of individual OABSS and urinary frequency per day results showed an apparent variation during the baseline phase in all participants and marked reduction in both indices in one participant (number 3) during the intervention that remained during the follow-up phase (relative to baseline; Figure 1). Visual analysis corresponds with the Tau-U effect size statistics. Only one out of four participants (number 3) presented with a statistically significant reduction in OABSS and urinary frequency per day following the photobiomodulation therapy. The effect size of intervention on OABSS varied from small to medium-to-high among patients during the intervention phase relative to the baseline phase with the highest Tau-U of -0.81 in participant 3 (P=0.001; Table 1), and this finding remained during the follow-up phase relative to baseline (Tau-U -0.76, p=0.007; Table1). Overall Tau-U score showed a trend towards a small effect size (reduction) of the intervention on OABSS during the intervention phase (Tau-U -0.22, P=0.125; Table 1) that remained during the follow-up phase (Tau-U -0.23, P=0.112; Table 1). The photobiomodulation therapy was associated with a statistically significant overall improvement in the urinary frequency per day during the intervention phase (Tau-U -0.44, p=0.003; Table 2) and the follow-up phase (Tau-U -0.32, p=0.003; Table 1). Finally, there is supportive evidence that participants with higher OABSS would respond better to the therapy (Pearson's correlation coefficient -0.94, p=0.056). This trend was not observed with the day urinary frequency (Pearson's correlation coefficient -0.30, p=0.694).
Interpretation of results
NIRL delivered via a nasal prong to patients with OAB was not associated with any adverse effects. Multiple-dose NIRL as a treatment for reducing OAB severity thus holds promise and justifies further investigation.