Abstract
In a controlled study, the effects of amitriptyline compared with that of a placebo in cats suffering from idiopathic Feline Lower Urinary Tract Disease (FLUTD) have been investigated. Thirty-six animals were selected by veterinary practitioners and treated with a placebo or 10 mg amitriptyline once daily. All animals received concomitant antibiotic treatment. A total of 24 cats were included in the final assessment of the results. The severity of symptoms before and after treatment were compared between groups and showed no significant difference. Results indicated that the 7-day course of 10 mg amitriptyline was not effective in the treatment of idiopathic FLUTD. Thus, it is considered not to be beneficial as a short-term therapy where the therapeutic results depend on peripheral effects of the drug. Long-term effects may be expected 4 or more weeks after the start of therapy and need to be further investigated.
Introduction
Diseases of the lower urinary tract in cats (feline lower urinary tract disease (FLUTD)) are common in veterinary practice. The prevalence of FLUTD in Europe is not known, but they are widely considered as one of the major diseases occurring in feline patients. In the United States, the incidence of this disease, defined as the number of new cases per year out of the average number of individuals in the population at risk, has been estimated to be 0.85%, representing up to 10% of veterinary clinic admissions of cats (Lawler et al 1985). FLUTD has a considerable socio-ethical impact on the owner of the diseased animal. Whilst the clinical symptoms are a cause of major distress in affected animals, inappropriate micturition in the owner's home is often present. Therefore, some owners consider taking their cat to an animal shelter, and even consider euthanasia following the years of recurrent problems (Chew et al 1998). This has been confirmed for the United States, where inappropriate micturition has been found to be the most common cause for relinquishing of the cats to animal shelters (Patronek et al 1996). As a consequence, there is a considerable need for treatments that effectively control the signs of FLUTD. Successful management of FLUTD is complicated by the chronic recurrence of the disease status in a substantial number of patients.
Current ideas on the aetiology of FLUTD have changed considerably, following the results of several prospective case studies in large numbers of affected cats. In one study, a total number of 141 cats, presenting with haematuria, dysuria, urethral obstruction or combinations of these signs were evaluated (Kruger et al 1991). Another study evaluated 109 non-obstructed cats with stranguria, hematuria, pollakiuria or urination in inappropriate locations (Buffington et al 1997). In both studies, a specific diagnosis could be made in approximately 45% of the patients, comprising obstructing crystalline matrix plugs, urolithiasis, anatomical defects, neoplasia and behavioural disorders. In less than 3% of all the cats, urinary tract infections (UTI) were found. In over half of the patients, no underlying cause for the clinical signs was identified. In addition, some patients showed normal urinalysis results. Thus, the term idiopathic FLUTD was introduced to describe the disease in the latter group of patients.
One of the drugs considered as potentially effective in the treatment of idiopathic FLUTD is the tricyclic antidepressant amitriptyline. It was hypothesised that idiopathic FLUTD resembles interstitial cystitis (IC) in humans. Amitriptyline has been used in women with IC since 1989 and was found to partially or completely relieve the symptoms in about 60% of patients (Hanno 1994). Several publications have described its use in cats, starting from 1994 (Buffington and Chew 1994), and it has been tested in an uncontrolled, long-term clinical trial (Buffington et al 1999). Thus, the aim of this study was to investigate the short-term effects of amitriptyline in cats suffering from idiopathic FLUTD, in a prospective placebo-controlled study.
Materials and methods
Study design
The study had a multi-centre, double-blind placebo-controlled design, and was run in 12 veterinary clinics in the Netherlands between March 1998 and July 1999. All the cats presented with signs suggesting FLUTD, such as dysuria, pollakiuria, hematuria and inappropriate urination in the owner's home. Cats having had at least one previous episode of FLUTD were considered for inclusion in the study. A written statement indicating the agreement of the owner for possible participation in the study was requested. On acceptance into the study, the patients received a placebo or amitriptyline for 7 days, both in combination with antibiotic treatment (see the subsequent discussion). After 7 days, the veterinary practitioner re-examined the patient; and after another 7 days, a final examination was carried out.
Clinical examination and inclusion criteria
The diagnostic work-up of the patients allocated to the study started with a clinical history and thorough physical examination. When no abnormalities were found, the cat was sedated using medetomidine (Domitor®; Pfizer Animal Health BV) as per the manufacturer's prescription. A blood sample was taken for biochemical analysis (urea, creatinine, alkaline phosphatase and alanine aminotransferase, fasting bile acids and total thyroxin). Ultrasonography of the lower urinary tract (as described by Cartee et al 1980) was conducted, followed by catheterisation of the bladder using a tomcat catheter (unspecified brands, as chosen by the practitioner). A mid-stream urine sample was collected (Biewenga and van Oosterom 1995) and urinalysis was carried out using a commercial dipstick (Multistix®10SG; Bayer) and refractometric analysis. Aliquots of the urine samples were diluted in a transport medium (Uricult®; Orion Diagnostics) and were subjected to microbiological analysis. Finally, atipamezole (Antesedan®; Pfizer Animal Health BV) was used to reverse sedation.
Cats were excluded from entering the study if signs of known urinary tract disease or any other serious condition were found during examination. Animals were also excluded if ultrasound indicated the presence of a bladder stone, neoplasia or congenital abnormalities of bladder and/or urethra. Similarly, values of pH ≥8 and/or protein ≥1 g/l during urinalysis were excluded. Cats were withdrawn from the study following a positive urine bacterial culture (≥104 CFU/ml), abnormal values in serum chemistry profile, or incomplete data sets.
Treatment
The dose of 10 mg amitriptyline (Amitriptyline Hydrochloride 10 mg; Centrafarm BV, Netherlands) per animal was used and given orally once daily. A specially manufactured placebo tablet was administered using the same dosing schedule. Owners were advised to administer the tablets in the evening, and were asked to record daily if they had administered the prescribed tablets. 10 mg/kg bodyweight amoxicillin-trihydrate (Paracilline®40 mg; Mycofarm BV, Netherlands) was also given orally twice daily.
Clinical evaluation
To assess the efficacy of treatment, the severity of symptoms at days 0, 7 and 14 were marked by the practitioner on a visual analogue scale: a vertical scale of exactly 100 mm in length, with values ranging from ‘0’ (healthy cat without urinary problems) to ‘100’ (severe symptoms of disease). These values, obtained at subsequent examinations, were compared and the relative changes in severity of symptoms were calculated. Both practitioner and owner were also asked to assess the overall result of treatment as: (1) complete cure, (2) improved, (3) no change, or (4) worsened.
During every visit, an intensive clinical examination was performed, focusing on possible side effects. Owners were asked to monitor the urination behaviour (frequency, duration and volume), level of activity and general attitude of their cats during the study. For this purpose, the investigator supplied a form on which owners could record their observations.
Statistics
Mean and SD were calculated for each group from the visual analogue scales. Values were compared using a Student's t-test. The significance level was determined at 5% (P<0.05). All other treatment-related values were analysed using a chi-square test, comparing ‘cured’ and ‘non-cured’ cats, and a Mann–Whitney U-test for all the investigator values. Safety data have been described in numbers or as median value and range, followed by Mann–Whitney U-test. Urinalysis, blood chemistry and ultrasound findings are presented as mean and SD or as descriptive statistics.
Results
Thirty-six feline patients were accepted for the study. They were gathered in six different veterinary practices. Two practitioners admitted 19 cats, all of which were included in the study. Both sexes were equally represented and had a mean age of 5.6±3.2 years. Eight of the cats had positive results in their bacteriological urinalysis. Escherichia coli was cultured in six cats, and Pseudomonas aeruginosa and coagulase-positive staphylococci both were cultured in one cat. After treatment of these cats with amoxicillin, signs resolved in five cats, two cats improved (one was infected with amoxicillin-resistant E coli) and results from one cat were doubtful. These cases were withdrawn, along with four other cases for which the pre-administration data remained incomplete.
Finally 24 cases were selected and divided into two treatment groups: 11 cases in the group treated with amitriptyline and 13 cases in the control group. In one case, treatment was ended after 6 days and this was regarded as a treatment failure.
Clinical observations prior to treatment
Owners often reported hematuria (11/24) and/or inappropriate urination (13/24). The number of recurrences in patients ranged from one to 15 times, and these were equally divided between the two groups. Most urine samples (19/24) were acidic, the pH median value being 6.5 (range, 6.0–8.0). All but two urine samples showed measurable protein levels (from 1+ to 3+), and the urine specific gravity median value was 1.028 (range, 1.010–1.050). Abnormal findings reported after ultrasonography included an abnormal thickened bladder wall in seven cats, in combination with echodense intraluminal material in two cats. The presence of echodense material in the bladder without other abnormalities was reported in one cat.
Changes in severity of symptoms, as recorded on the visual analogue scale, were assessed for all the patients after 7 days of treatment (Fig 1), and the group values were statistically compared.
00004-4/unzip/10.1016_S1098-612X(03)00004-4-fig1.png)
Change in severity of clinical symptoms after therapy with amitriptyline compared with a placebo (day 7): results of the virtual analogue scale.
The statistical evaluation revealed no significant difference between the groups (P<0.2). At the final examination (day 14), the difference between groups was still insignificant (P<0.5).
In addition, no significant differences in overall response to treatment between the amitriptyline-treated group and the control group were found (Table 1), either for investigator response (P<0.2) or owner response (P<0.5). A statistical analysis on all the values was also performed using a Mann–Whitney U-test, which confirmed the outcome of the chi-square test (P=0.13).
Overall response to treatment: ‘complete cure‘ (day 14)
00004-4/unzip/10.1016_S1098-612X(03)00004-4-table1.png)
The use of amitriptyline was significantly (P=0.02) associated with a change in general attitude and decreased level of activity, when compared with the control group. Only two owners reported mild side effects. In one cat on amitriptyline, ataxia of the hind legs was observed and another cat showed desirablebehavioural changes in being less aggressive.
Discussion
In this study, the potential beneficial effect of amitriptyline on idiopathic FLUTD in cats was investigated. Amitriptyline is a tricyclic antidepressant drug (TCA) with a typical, dibenzocycloheptene-derived, three-ring molecule. It belongs to a group of drugs that, by their pharmacological properties, are referred to as ‘serotonin re-uptake inhibitors’ (SRI). Currently, nine analogues of this drug are available, including nortriptyline (a metabolite of amitriptyline), imipramine, desipramine, doxepine and protriptyline (Baldessarini 2001). In veterinary medicine, TCAs are used in the treatment of a variety of behavioural disorders, including separation anxiety in dogs and general anxiety that may be related to micturiction disorders, such as spraying (Overall 1997). The mechanisms by which TCAs exert their effects are only partially understood. At least three major pharmacological actions exist: (1) potentiation of the actions of biogenic amines (norepinephrine, dopamine and serotonin) in the CNS by inhibiting their re-uptake at pre-synaptic nerve terminals; (2) central and peripheral anticholinergic effects at some, but not all, sites; (3) blockade of H1-histaminergic receptors resulting in mild sedation.
Blockade of amine re-uptake is promptly established, but the antidepressant effect in humans typically requires administration of the drug for several weeks. When used in animals for behavioural therapy, effects are reported to commence at the earliest after about 4 weeks, but may require several months of therapy to reverse the clinical symptoms (Mertens and Dodman 1998). Weight gain is a common side effect for most antidepressants in humans, and this effect has been established for amitriptyline in cats as well (Chew et al 1998).
Specific pharmacokinetic data related to the use of amitriptyline in cats are not available. Variation coefficients up to 30–50% of human plasma levels have been noted after administration of a constant dose of TCAs (Baldessarini 2001). Individual variation in kinetics and, hence, the efficacy of TCAs are well-known obstacles in human therapy, and may be equally important in cats.
The results of this study do not support the hypothesis that cats with idiopathic FLUTD benefit from treatment with 10 mg amitriptyline given once daily for 7 days. The dose used in this study was based on previous studies (Borchelt and Voith 1981, Marder 1991), but may be inappropriate for individual patients considering the earlier-mentioned experience in human patients. As the clinical signs were not monitored during treatment, amitriptyline may have led to earlier remission of signs during the treatment when compared with the placebo. This has recently been reported in a controlled study in which amitriptyline was administered for 7 days in hospitalised cats (Kruger et al 2001). Signs of pollakiuria were described to have resolved significantly earlier compared with the control group, while haematuria persisted. In our study, symptoms were monitored and were described daily by owners, and although this procedure results in less precise data on the progress ofdisease, any significant changes would have been recorded by the veterinarian during the final assessments of the patients.
The concomitant use of antibiotic treatment in this study was undertaken so as not to leave cats with potential UTI untreated, while awaiting results of bacterial culture. Given the fact that positive urine bacterial cultures were found in 25% (8/32) of the cats, the use of the antibiotic in this study seemed necessary. Notably, the percentage of UTI patients was substantially higher than was found during earlier studies on the aetiology of FLUTD (Buffington et al 1997, Kruger et al 1991). This may relate to the larger number of cases in these studies or to the fact that they were performed at university hospitals, thus focusing on a pre-selected population of patients. Another reason for the observed difference might be the method by which urine samples were obtained in our study. However, given the findings on bacterial cultures being high numbers of singlespecies of bacteria, this should be considered unlikely. Although cystocentesis is the gold standard for obtaining urine for bacterial culture, catheterisation was instead performed to investigate possible obstructive lower urinary tract disease, at the same time as obtaining a urine sample.
There are several theories regarding the potential beneficial effects of amitriptyline in idiopathic FLUTD. Amitriptyline is a potent H1-receptor antagonist and much less potent towards H2-receptors (Richelson 1979), and has been found to inhibit the release of histamine from in vitro mast cells (Theoharides 1996). Hypothetically, this may have an effect on the vascular and inflammatory changes in the bladder wall, which may be observed during cystoscopic examination of the bladder in the cats with idiopathic cystitis (Buffington et al 1996). However, such an effect was not observed during a study in which 15 cats received long-term treatment with amitriptyline (Chew et al 1998). Even though complete remission of clinical signs was reported in nine of the 15 cats, no amelioration in cystoscopic abnormalities was found even after 12 months of therapy. Thus, even if we assume that the antihistaminic action contributes to the remission of clinical signs, the use of amitriptyline as the drug of choice for its effect on mast cells would be prudent and should be weighed against the potentially strong central antihistaminic effect causing sedation and drowsiness.
Analgesic effects in humans have been reported starting from 3–7 days (Eschalier 1990) up to 4 weeks (Sharav et al 1987) after the onset of treatment. It has been hypothesised that amitriptyline could exert its analgesic effect by inhibiting norepinephrine re-uptake (Chew et al 1998), as indicated in a study on the effect of SRIs in human patients suffering from diabetic neuropathy (Max et al 1992). However, amitriptyline is considered to be a weak norepinephrine re-uptake inhibitor in the group of TCAs (Baldessarini 2001; Overall 1997), and other drugs, such as desipramine and protriptyline, may be expected to be more potent with regard to this effect.
The strong anticholinergic effect (Snyder and Yamamura 1977) may lead to decreased contractility of the detrusor muscle, shifting the α1-adrenergic response towards increased smooth muscle relaxation of the internal bladder sphincter at the same time (U'Prichard et al 1978). The net result is an improvement of bladder function and possible reduction of signs of pollakiuria. Finally, amitriptyline may inhibit segmental transmission of wide dynamic range (WDR)neurons in the trigeminal nucleus, which could lead to inhibitory effects on sensory nerves (Chew et al 1998). This effect has been investigated in cats during the studies on the mechanism of action of drugs effective in the treatment of trigeminal neuralgia in humans (Fromm et al 1991). Further research would help to assess whether these findings can be extrapolated to nerves related to the sensory innervation of the bladder.
As we look at the pharmacological properties of amitriptyline, it should be taken into consideration that in this study, only the short-term effects have been studied at a single dose. Since the long-term effects are expected to occur only after several weeks of treatment, long-term controlled studies with amitriptyline are recommended to establish whether cats with idiopathic FLUTD will benefit from the therapeutic use of amitriptyline. In addition, larger numbers of patients, than evaluated in this study, are needed to evaluate the significance of the findings observed in the two treatment groups. Finally, consideration should be given to investigating the specific effects of drugs acting directly on the urinary bladder, as this may lead to a better understanding of the aetiology of FLUTD.
Footnotes
Acknowledgments
The authors would like to thank Intervet International BV, Netherlands, for the financial support and for the preparation of the placebo tablets. The technical support from the diagnostic laboratories of the Veterinary Faculty, Utrecht, in the bacteriological investigations of the urine samples is gratefully acknowledged. Finally, the authors would like to thank Dr S. Bull and Dr P. Barber for their help while preparing the manuscript.