Background
The efficacy of intradetrusor onabotulinumtoxinA injections for the management of idiopathic overactive bladder has been well-established. The injections are typically performed in the office setting using local analgesia, most commonly a 20 to 30-minute intravesical instillation of lidocaine. There are limited data evaluating alternative bladder analgesics.
Objective
To compare pain scores with preprocedure oral phenazopyridine vs intravesical lidocaine in women undergoing intradetrusor onabotulinumtoxinA injections for idiopathic overactive bladder.
Study Design
Nonpregnant adult females with idiopathic overactive bladder, scheduled for office injection of 100 units of intradetrusor onabotulinumtoxinA were randomized to either 200 mg of oral phenazopyridine taken 1 to 2 hours preprocedure or a 20-minute preprocedure intravesical instillation of 50 mL of 2% lidocaine. We excluded participants with neurogenic bladders, and those who had received intradetrusor onabotulinumtoxinA injections in the previous 12 months. The primary outcome was pain measured by a 100-mm visual analog scale. Demographic characteristics and overall satisfaction with the procedure were also recorded. Providers answered questions about cystoscopic visualization, ease of procedure, and perception of participant comfort. Prespecified noninferiority margin was set to equal the anticipated minimum clinically important difference of 14 mm. A planned sample of 100 participants, 50 in each treatment arm, provided 80% power to detect noninferiority at a significance level of.05. We performed a modified intention-to-treat analysis and compared variables with the t test or the Fisher exact test.
Results
A total of 111 participants were enrolled, and complete data were obtained for 100 participants; 47 participants were randomized to phenazopyridine and 53 to lidocaine. Baseline characteristics did not differ between groups. There were 19.6% and 20.8% of participants in the phenazopyridine and lidocaine groups, respectively, who previously underwent intradetrusor onabotulinumtoxinA injections. The mean postprocedure pain was 2.7 mm lower in the phenazopyridine group than in the lidocaine group (95% confidence interval, −11.3 to 10.7), demonstrating noninferiority. More than 90% of participants in both groups stated that the pain was tolerable. Slightly more participants reported being “very satisfied” in the lidocaine group, although this was not statistically significant (50.0% vs 40.4%; P =.34). Providers reported clear visualization in 89.4% of participants in the phenazopyridine group and in 100% of participants in the lidocaine group ( P =.02). Provider perception of participant comfort and overall ease of procedure were not different between groups. Length of time in the exam room was significantly shorter in the phenazopyridine than in the lidocaine group (44.4 vs 57.5 minutes; P =.0003).
Conclusion
In women receiving intradetrusor onabotulinumtoxinA injections for idiopathic overactive bladder, oral phenazopyridine was noninferior to intravesical lidocaine for procedural pain control. Phenazopyridine is well-tolerated by participants, allows for the procedure to be performed with similar ease, and is associated with shorter appointment times.
Introduction
Idiopathic overactive bladder (OAB) is prevalent, affecting an estimated 30% of American women. It profoundly impacts quality of life, and represents an enormous economic burden to the healthcare system. , As recommended by the American Urological Association, patients who experience inadequate relief from conservative therapies may proceed with third-line therapy such as intradetrusor onabotulinumtoxinA injections. Level I evidence supports the efficacy of onabotulinumtoxinA in treating idiopathic OAB and, as opposed to alternative third-line therapies for OAB, onabotulinumtoxinA injections can be performed in the office setting, presuming adequate analgesia is attained.
Why was this study conducted?
This study was conducted to compare oral phenazopyridine with intravesical lidocaine for analgesia during office-based injection of onabotulinumtoxinA into the detrusor muscle of participants with overactive bladder.
Key findings
Phenazopyridine is noninferior to lidocaine for procedural analgesia.
What does this add to what is known?
Very little was previously known about procedural pain scores or analgesic efficacy of either medication for this indication. We proposed an acceptable oral alternative to the traditionally used intravesical lidocaine instillation.
However, to date, research is lacking with respect to the most effective analgesic approach to office-based injections of onabotulinumtoxinA. The most widely used method is intravesical lidocaine instillation. This is based on small studies in the urology literature, which describe adequate pain relief using intravesical lidocaine before bladder biopsies or fulguration. , However, it is unclear whether this method is sufficient or appropriate for use with onabotulinumtoxinA injections, and comparative studies are lacking. In addition, lidocaine is a weak base that is ionized in the relatively acidic environment within the bladder. Once ionized, the drug likely has poor urothelial penetration and may therefore be unable to provide adequate analgesic effect. Buffered lidocaine has been explored as a possible alternative that may improve analgesic effect; however, this approach results in significant systemic absorption, which may pose additional risk. , In addition, the use of lidocaine may increase appointment length because it is generally instilled and retained in the bladder for 20 to 30 minutes before the start of the procedure.
Potential alternatives to lidocaine exist. Phenazopyridine is a well-known bladder analgesic and is typically used to provide symptomatic relief of bladder pain in conditions such as cystitis and urethritis. Its exact mechanism of action is not known. A study performed on rats evaluated the effects of phenazopyridine on afferent activity of Aᵟ-fibers and C-fibers originating from the bladder. Phenazopyridine substantially decreased Aᵟ-fiber activity, but not C-fiber activity. There are otherwise minimal data to illustrate the effect of phenazopyridine on the bladder. Considering the widespread use of phenazopyridine as a bladder analgesic and the biochemical evidence of decreased afferent pain signals, it stands to reason that phenazopyridine could be a viable alternative to intravesical lidocaine instillation for office onabotulinumtoxinA procedures.
The objective of this study was to compare intravesical lidocaine instillation with oral phenazopyridine to determine their relative effects on periprocedural pain scores, overall participant satisfaction with analgesia, physician perception of ease of procedure, and appointment efficiency.
Materials and Methods
We conducted a single-institution, randomized, noninferiority trial comparing the efficacy of oral phenazopyridine with intravesical lidocaine for analgesia during office-based injection of intradetrusor onabotulinumtoxinA for idiopathic OAB. This study was approved by the medical center’s institutional review board, and all participants signed written informed consent before enrollment. Adult women with idiopathic OAB who were scheduled for injection of intradetrusor onabotulinumtoxinA were recruited from a single, tertiary-care, academic practice. Participants were considered ineligible if they had routine procedural contraindications such as active urinary tract infection, botulinum toxin use for other indications such that bladder injection would exceed the recommended maximum dose, or inability or unwillingness to perform self-catheterization. Participants with a history of pelvic radiation, known urothelial malignancy, a surgically altered detrusor muscle, neurogenic detrusor overactivity, planned injection of >100 units of onabotulinumtoxinA, or allergies or other medical ineligibility for either study medication were also excluded. Participants were also ineligible if they had received intradetrusor onabotulinumtoxinA injections in the 12 months preceding study enrollment.
Eligible participants were offered study enrollment at a routine office visit before their scheduled intradetrusor onabotulinumtoxinA injections. Once enrolled, they were randomized to either a 50-mL intravesical instillation of 2% lidocaine retained within the bladder for 20 to 30 minutes immediately before the procedure or to a single dosage of 200-mg oral phenazopyridine taken 1 to 2 hours before the procedure start. Patients randomized to phenazopyridine were prescribed the medication, instructed to obtain it from their pharmacy at their convenience, and take it at home 1 to 2 hours before their scheduled procedure. Patients randomized to the lidocaine group underwent instillation of 50 mL of 2% lidocaine into the bladder via a sterile 14-French straight catheter that was placed after preparing the urethra with povidone-iodine (Betadine; Avrio Health L.P., Stamford, CT). The catheter was immediately removed and the lidocaine was retained within the bladder until procedure start time 20 to 30 minutes later. Patients in both groups received 10 mL of 2% lidocaine jelly per urethra before introducing the cystoscope.
Randomization used computer-generated random numbers in permuted blocks of random size. Allocation was concealed by sealed, opaque envelopes. Masking of clinicians and participants was not feasible for this study because phenazopyridine stains the urine orange, and an acceptable placebo does not exist.
The primary outcome was procedural pain as measured by a 100-mm visual analog scale (VAS). The VAS system is a unidimensional pain scale, which can be administered quickly with minimal administrative effort, and is easily understood by participants. The VAS was chosen over the more traditional, 0 to 10 numerical rating scale because it is considered to be a more sensitive tool for assessing acute pain and is the most widely used unidimensional pain scale in the scientific literature. , The VAS was administered preprocedure and immediately postprocedure, at which time participants were asked to rate the highest level of pain experienced during the procedure. Secondary outcomes were overall participant satisfaction with the procedure, physician perception of visualization and ease of performing the procedure, and appointment length.
Data on pain scores during office-based bladder procedures are scarce. We based our sample size calculations on 2 small cohort studies reporting pain during bladder biopsy; however, the statistical analysis in each was limited. In these studies, the mean 100-mm VAS score (converted from a 5-point VAS to be comparable with our planned analysis) ranged from 32 mm with biopsy to 54 mm with fulguration. , No standard deviation was reported in either study. From the gynecology literature, 1 study reporting pain with office-based diagnostic hysteroscopy reported mean pain of 57.5 mm (converted from a 20-point VAS), with a standard deviation of 15 to 25 mm.
Existing data suggest that the minimum clinically important difference (MCID) in 100-mm VAS scores varies on the basis of the reported level of pain. For pain levels of <40, 40 to 70, and >70 mm, the MCIDs are 6 (4–8) mm, 13 (11–14) mm, and 21 (20–23) mm, respectively. Therefore, we assumed a mean pain score of 40 mm (based on bladder biopsy/fulguration data) with a standard deviation of 25 mm (based on benign gynecology data), leading to an MCID of 14 mm. The noninferiority margin was prespecified to equal the MCID of 14 mm. A planned sample of 100 participants provided 80% power to detect noninferiority at a significance level of.05.
Data analysis was performed using SAS, version 9.4 (SAS Institute, Cary, NC). Descriptive statistics were used to assess the balance of baseline characteristics between groups. The primary analysis was modified intention-to-treat. Because there were no participants who crossed over between groups, and the participants who were lost to follow-up were excluded from analysis because of lack of data, the intention-to-treat analysis was equivalent to a per-protocol analysis. Outcomes were compared between groups using the Student t -test, chi square test, and Wilcoxon rank-sum test, as appropriate. A P value of <.05 was considered statistically significant.
Results
Among the 255 participants who were screened for eligibility, 144 were excluded because of not meeting inclusion criteria or declining to participate ( Figure ). A total of 111 participants were enrolled and underwent randomization, among whom 54 were allocated to phenazopyridine and 57 to lidocaine. Three participants from the phenazopyridine group and 1 participant in the lidocaine group voluntarily withdrew from the study after undergoing randomization but before receiving the respective intervention. One participant in the phenazopyridine group was withdrawn from the study because of a protocol violation that was recognized after randomization; the participant was scheduled to receive 150 units of intradetrusor onabotulinumtoxinA injections rather than the 100 units specified as an inclusion criterion in the protocol. This did not result in harm to the participant.
Table 1 provides details pertaining to participants’ baseline characteristics, which did not differ between groups. Most participants identified as White and not Hispanic or Latino. More than half of the participants were married or living with a partner, and most had completed at least high school or high school equivalency. Most participants were insured through Medicare or Medicaid. The overwhelming majority of participants had not previously received intradetrusor onabotulinumtoxinA injections, and preprocedure pain scores were similar between the 2 groups ( Table 2 ). Anxiety and depression were common comorbid conditions in both groups. The incidence of chronic pain conditions such as fibromyalgia or interstitial cystitis was low in both groups.
| Demographic variables | Total (N=100) | Oral phenazopyridine (N=47) | Intravesical lidocaine (N=53) |
|---|---|---|---|
| Age (y) | (n=97) | (n=45) | (n=52) |
| Mean (SD) | 66.0 (12.7) | 67.6 (11.2) | 64.6 (13.8) |
| Median (range) | 67 (25–87) | 68 (36–86) | 66.5 (25–87) |
| Race, n (%) | |||
| American Indian/Alaska Native | 2 (2.0) | 1 (2.1) | 1 (1.9) |
| Black/African American | 3 (3.0) | 0 (0.0) | 3 (5.7) |
| White | 83 (83.0) | 43 (91.5) | 40 (75.5) |
| Multiracial | 2 (2.0) | 1 (2.1) | 1 (1.9) |
| Unknown or not reported | 10 (10.0) | 2 (4.3) | 8 (15.1) |
| Ethnicity, n (%) | (n=98) | (n=51) | |
| Hispanic or Latino | 11 (11.2) | 2 (4.3) | 9 (17.6) |
| Not Hispanic or Latino | 81 (82.7) | 44 (93.6) | 37 (72.5) |
| Unknown or not reported | 6 (6.1) | 1 (2.1) | 5 (9.8) |
| Educational attainment, n (%) | (n=99) | (n=52) | |
| Less than high school | 7 (7.1) | 2 (4.3) | 5 (9.6) |
| High school or GED | 32 (32.3) | 15 (31.9) | 17 (32.7) |
| Associate college degree | 22 (22.2) | 13 (27.7) | 9 (17.3) |
| Four-year college degree | 19 (19.2) | 8 (17.0) | 11 (21.2) |
| Graduate degree | 18 (18.2) | 9 (19.1) | 9 (17.3) |
| Unknown or not reported | 1 (1.0) | 0 (0.0) | 1 (1.9) |
| Marital status, n (%) | (n=99) | (n=52) | |
| Single (never married) | 13 (13.1) | 2 (4.3) | 11 (21.2) |
| Married or living with partner | 54 (54.5) | 25 (53.2) | 29 (55.8) |
| Divorced or separated | 11 (11.1) | 7 (14.9) | 4 (7.7) |
| Widowed | 21 (21.2) | 13 (27.7) | 8 (15.4) |
| Health insurance, n (%) | (n=99) | (n=52) | |
| Private | 27 (27.3) | 12 (25.5) | 15 (28.8) |
| Medicare or Medicaid | 47 (47.5) | 20 (42.6) | 27 (51.9) |
| Private + Medicare or Medicaid | 24 (24.2) | 15 (31.9) | 9 (17.3) |
| Unknown or not reported | 1 (1.0) | 0 (0.0) | 1 (1.9) |
| BMI (kg/m 2 ) | (n=99) | (n=52) | |
| Mean (SD) | 32.6 (7.0) | 31.5 (5.8) | 33.5 (7.9) |
| Median (range) | 32.5 (18.6–62.4) | 32.0 (18.6–45.0) | 33.2 (20.9–62.4) |
| Previous Botox, n (%) | (n=99) | (n=46) | |
| Yes | 20 (20.2) | 9 (19.6) | 11 (20.8) |
| No | 79 (79.8) | 37 (80.4) | 42 (79.2) |
| Other medical problems, n (%) | |||
| Anxiety | 31 (31.0) | 13 (27.7) | 18 (34.0) |
| Depression | 35 (35.0) | 18 (38.3) | 17 (32.1) |
| Interstitial cystitis or painful bladder syndrome | 2 (2.0) | 0 (0.0) | 2 (3.8) |
| Fibromyalgia | 3 (3.0) | 2 (4.3) | 1 (1.9) |
| Other chronic pain syndrome | 5 (5.0) | 1 (2.1) | 4 (7.5) |
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