Canine Urinary Incontinence Successfully Treated by Homeopathic Medicine: A Real-World Clinical Evidence Panel Study

Background Medical Condition and Epidemiology

Urinary incontinence (UI) or involuntary discharge of urine is mainly due to insufficient closure of the urinary sphincter. UI in animals, mainly in companion species, such as cats and dogs, is a main concern in veterinary healthcare. There are multiple reasons for UI in pets including stress (emotions), higher age, structural and functional problems of the bladder or the ureter, increased bodyweight, immobility, and surgical neutering of the animal [1, 2, 3]. While UI is affected by age and body weight it is not related to the age at the time of neutering surgery [2]. However, there is a greater prevalence in some breeds [3]. The above four causes together are minor contributors (< 1%) to the reported incidence of urinary incontinence [4], while its major contributor (20%) is incontinence following neutering of pets, especially of females [1]. However, there is gross underreporting of the problem, as deduced from the comparison between institutionalized animals with the overall population. Most notably non-iatrogenic UI is grossly underestimated, especially in smaller veterinary practices [5]. Due to the requirements of care and other associated challenges, UI is among the common causes for requesting euthanasia [6]. The cost of UI treatment ranges from approximately $20 to $150 per week as per analysis of the cost of bladder control medicines available online. As UI is not a terminal illness and is not time-bound, the main concern for pet owners concerning treatment may be cost, which in turn adds to socioeconomic challenges.

Landscape of Current Therapies

The major focus of treatment of UI has been on post- neutering UI, because only about one fifth of animals with UI have causes other than neutering surgery [3]. While the major contributing factor is still surgical neutering [1, 2, 3], overactive bladder syndrome, stress incontinence, and overflow incontinence [3] also have a role to play. Another possible reason for this focus is a relatively clear understanding of pathophysiology of post-neutering iatrogenic UI, as compared with other complex mechanisms of urethral sphincter mechanism incompetence (USMI)[7]. In post-neutering UI reduced bladder responsiveness to muscarinic stimulation and increased collagen in the bladder wall in females are predominant mechanisms [8]. It is well understood that in post-neutering UI, the muscarinic receptor effector pathways are a more easily identified therapeutic target for acquired urinary incontinence treatment. Hence, this challenge is easier to treat using various agents like gonadotrophins [8].

The current therapy for UI can be broadly divided into three major groups that include medicinal therapy, surgical treatment, supportive and conservative therapies, and a few other approaches, including increasing urethral bulk. While multiple studies performed on small samples are published towards justification of efficacy on particular causes, most of these studies focus only on the hormonal (senile or post- neutering) causes of urinary leakage. Among the medicines used, alpha-adrenergic agents, phenylpropanolamine hydrochloride is the most common and this treatment has been approved by US FDA for once daily medication [9]. However, there are limitations for this therapy in many causes, such as ectopic ureters and prostatic cysts, also the cost of therapy is extremely high. The surgical management of the condition is the second most common therapy, however this therapy is also expensive and includes a risk of disability [10].

Rationale of the Current Research

Considering the current landscape of medical and surgical therapy for canine urinary incontinence the major concerns are wide-spread applicability of the therapy, ease of availability, higher cost and in surgical cases, higher risk of disability. Hence, there is a need for a safer, cost effective and easy to handle medication. Commonly, homeopathic medicines are used either as complementary, or as an alternative to the current therapy and is observed to reduce the treatment time in humans [11]. There have been multiple rejections of homeopathic efficacy in the treatment of UI with such rejections being cited as due to the lack of scientific evidence. However, potential exists for homeopathic medicines to be the treatment of choice in various veterinary conditions [12, 13].

Principally the homeopathic medicines used are simple single medicines [14]. Whereas, the use of complex or combined (mixed) remedies is often favored when there is a lack of subjective symptoms that generally makes the selection of a simple single remedy unviable. Hence, despite being a deviation from principles, pragmatic use of combinations has become popular in a few critical conditions and in veterinary use with mixed outcomes [15], mandating the generation of evidence for every combination product in the given indication. There is subset-based evidence of homeopathy improving UI from a large canine and feline study [16]. Hence, this study was conducted to determine the efficacy and safety of 'Leaks No More' combination homeopathic medicine in canine UI.

Questionnaire Design and Response Collection

The questionnaire used for collection of the data included species, breed, age, sex, whether or not neutered, weight (lb), diagnosis, tenure of incontinence (months), dose, frequency, mode of dispensing, relief time, relapse, previous treatment, efficacy of previous treatment, and was the medicine continued. Of these, the last three questions were optional. Methodologically, most studies, referenced by this paper, have owner reported outcomes with continence improvement as the parameter of therapy efficacy [18-

25]. This study also included owner reported outcomes of continence improvement as the primary response of the study. The study was a patient-centric design, where the owner of the pet was asked to respond to a supervised survey directly. In all, 16 responses were collected from the two surveys.

Demographics Data Panel Presentation

For APVMA respondents the precursors of urinary incontinence viz. age percentile, body weight percentile, tenure of incontinence, and effectiveness of the prior medication was taken as plotting axes (Figure 1). All the ten panels of the APVMA responses were overlapped. The responses showed concentric circles of similar effective area. From this, it can be inferred that the effect of 'Leaks No More' in control of urinary incontinence is similar in all types of predisposing risk factors.

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Similar analysis was done for responses from the university college, with fewer data points available viz. age percentile, weight percentile and effectiveness of previous treatment. The effect area of the graph in all these overlapped panels was similar in magnitude (Figure 2).

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The data missing at random was reconstructed using the sample means. The interim Cohen’s Kappa for the APVMA group was on average of 0.7, for the university group was 0.6 and the interim between the two groups was 0.63 (χ2= 0.14, Pearson R = 0.98) p<0.03), meaning that there is an agreement between the two groups of surveys. Hence, these two surveys were merged for collective analysis, with use of overall mean wherever required for reconstruction of data missing at random.

The age of animals was 11.5±4.40 years. However,

considering the variability among the lifespans of different breeds, the age was considered with a percentile rank of the upper normal limit of the confidence interval of breed population [18]. The mean weight of the sample was 44.5±37.3. However, variability of weight is significantly higher among various species. Hence, percentile of weight (109.1±63.8) against the upper normal limit was taken for determination, which revealed that a significant population was overweight. 100% population of dogs were neutered and most (75%) of the population was female, making the group overall challenging for treatment (Table 1).

Primarily, the incontinence was a nocturnal type (81.25%) and among the remaining group as well, the nocturnal incontinence was observed with senile incontinence of random leaks. The overall tenure of leak was 12.55 ± 9.11 months. The median value of the dataset (12) was taken to reconstruct the data missing at random. While this value could be used in the data completely missing at random from the University College dataset, to avoid bias, the dataset was excluded from the analysis of tenure, as there was no major effect of this parameter on severity of disease or on the outcomes (Table 2).

In 6 (37.5%) animals the medication was given in water, in 8 (50%) medication was given in food and in 2 (12.5%) oral administration was done. The median dose given was 2 drops, with a maximum of 5 drops and minimum of 1 drop given once a day (3, 18.75%), twice a day (5, 33.33%) thrice a day (1, 6.25%). The data of daily frequency was not available for the University College dataset, hence the data missing completely at random was excluded. (Table 3).

All owners reported improvement of urinary leakage in the 16 (100%) participating animals, with only 2 (12.5%) animals having a relapse of symptoms. Most of the animals (15, 93.75%) improved within a week and the median time to relief was 3 [1. 6.5] days. Only one (6.25%) extreme outlier was observed where the improvement time was 60 days. This value appears to be a real outlier as Grubb’s G in the given data set is less than 5 and P-value is less than 0.0001 (Figure 3). Considering this and the strength of statistics of correlation of the data parameters (κ=0.63, χ2= 0.14, Pearson R = 0.98, p<0.03) for this analysis, the missing data for University College was reconstructed using median time to improvement (3 days) (Table 4).

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In the entire group, no adverse event was reported by the owners of the pets. In 7 out of 10 (70%) APVMA respondents, the owners continued medication to their pets despite improvement. The data of continuation of medication in the University College dataset was not available.

Analysis of Bias By Agreement Of Outcomes By Breed

The analysis of co-agreement among various dog breeds did not give significant analysis of agreement. The only significance observed between the overall results with Mixed, Greyhound, Doberman, and Shih Tzu had limited statistical significance. These results are in agreement with the anticipated outcomes of a proof-of-concept study. Hence, this is evidence of unbiasedness, impartiality, and reliability of the data (Effect size = 0.71, p=0.12).