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Is Alpha-casozepine Efficacious at Reducing Anxiety in Dogs?
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Clinical bottom line
There is currently no evidence to show that alpha-casozepine is effective as an anxiolytic when administered to dogs shortly (minutes to a few days) before exposure to an anxiety provoking stressor. There is limited and weak evidence to suggest that it may have a role to play in reducing anxiety in dogs over the medium to longer term but the available evidence is of low quality and / or high risk of bias, with confounding variables providing alternative explanations for the findings. More research is needed in this area.
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Appraisal, application and reflection
Three peer reviewed papers were identified that either partially or fully addressed the PICO. Two of these studies (Palestrini et al., 2010; Kato et al., 2012) investigated the use of diets with added alpha-casozepine, though, in the Kato et al. (2012) study the diet was also supplemented with another compound (tryptophan) thought to have anxiolytic properties. The remaining study (Beata et al., 2007) investigated the use of a daily capsule of alpha-casozepine. The two studies focused on dietary interventions (Palestrini et al, 2010; Kato et al., 2012) used a placebo-controlled study design, whereas Beata et al. (2007) compared alpha-casozepine to another intervention (selegiline) that was already used commercially as an anxiolytic.
All of the studies focus on the potential anxiety-reducing effects of alpha-casozepine when administered in the medium to long term. Time from baseline measurement to the first and last assessment of anxiety ranged from 14-56 days (Beata et al., 2007), c.30-68/69 days (Palestrini et al. 2012) or 7 weeks (one defined timepoint) (Kato et al. 2012). The Palestrini et al. (2010) study also undertook an assessment of the dogs at the start of administering the diet (separate to an additional set of baseline measurements taken immediately before starting the diet). However, there is insufficient study detail to define the exact details here and the number of days that comprised this phase is uncertain. Furthermore, as no significant differences were identified between this and the pre-diet baseline measurements, it is clear that there are no studies that found a significant effect of alpha-casozepine on indices of anxiety in the short term. Further, no studies were identified that looked at the effects of alpha-casozepine to a dog shortly before (e.g. minutes to a few days) exposure to a novel, or intermittent stressor (e.g. fireworks). Thus, there is currently no research evidence to support recommending the use of alpha-casozepine to clients seeking a quick acting anxiolytic product to alleviate short term stressors in the dog’s immediate or short term future.
All three of the studies that examined the effect of alpha-casozepine administration in the medium-long-term of indices of anxiety were problematic in terms of experimental design. Of the studies that looked at the effect of alpha-casozepine, the industry-sponsored study by Beata et al. (2007) offered the weakest experimental design and the authors appear unaware of this limitation as the conclusions that they draw are misleading. Equivalence and / or non-inferiority type studies in which a new treatment is compared to an existing treatment are increasingly commonplace in medical research and justified as removing the ethical issues of not treating some patients at all (or giving a placebo). Beata et al. (2007) adopt this approach, but their study design also includes a behavioural modification programme (BMP) alongside each of the anxiolytic products compared. This represents a confounding variable. As a consequence, even though their findings appear to indicate that alpha-casozepine has a similar efficacy as selegiline, based on their study design, the level of efficacy (from no effect to very effective) cannot be determined for either product as the effect of BMP is also unknown. This problem is compounded by their exclusion criteria as they systematically exclude any dogs that have already received BMP. Thus, it is not possible for the authors to justify their conclusions by the claim that, prior to starting anxiolytic therapy, these dogs had failed to respond to the BMP. Though even this appeal would be sensitive to the effects of time spent implementing a BMP on indices of anxiety reduction. Any appeal to the efficacy of alpha-casozepine would require appeal to the wider literature demonstrating an effect of selegiline per se on indices of anxiety in the dog and the inherent limitations and problems that entails. Thus, this study fails to address adequately the PICO posed in the Knowledge Summary.
Of the three studies, the Palestrini et al. (2010) most successfully set up their treatment groups to address the PICO. The two diets compared are identical other than the addition of caseinate hydrolysate (the milk protein isolate containing alpha-casozepine) and the dogs are not undergoing a behavioural modification programme. However, they fail to state the inclusion rate of the caseinate hydrolysate and the dogs were allowed to consume the diet on an ad libitum basis so individual dog exposure to the active ingredient was variable. One of the strengths of this study is that they also include a non-anxious group of dogs that are also randomly allocated to receive either the experimental or control diets. This potentially allowed them to identify whether any behavioural changes observed were due to other, non-anxiety based, properties of alpha-casozepine. However, the sample sizes utilised in this study were small to start with (n = 8 per sub-group), and they took the further, questionable, step at the end of data collection, of retrospectively removing from the main analysis, three of the dogs in the anxious group. They fail to report which of the treatment groups (experimental versus control diet) these dogs were allocated to and this means that one of these subgroups (crucial to answering the PICO) may have had as few as 5 dogs in it. Frequently, the paper moves from comparing diet groups (the aim of the study) to comparing the responses of anxious and non-anxious dogs and, therefore, fails to address the PICO at many points. There is some evidence (cortisol, reactivity evaluation form) to suggest the experimental diet reduced anxiety in anxious dogs by the end of the study, but most other physiological or behavioural parameters were either not affected by treatment or the findings are unreported. Poor data handling and reporting (see limitations) further limit the ability of the reader to draw meaningful inferences from the findings of this study. External validity is also questionable: with a captive-bred, born, reared and studied population of laboratory beagles and a maximum sample size per group of eight dogs (or lower), it is questionable how well any findings could be extrapolated to the pet population, with their varying genetic history and life time experiences.
Unfortunately, the final study (Kato et al. 2012) is also problematic in terms of addressing the PICO. In its defence, this industry sponsored study was not set up specifically to study alpha-casozepine but rather the effects of feeding a diet containing both alpha-casozepine and tryptophan on longer term indices of anxiety in the pet dog. Thus, the confounding variable of these additives to the diet exists for the purpose of the PICO but not for the purpose of the original study. However, the treatment diets were still not tightly controlled with the two diets varying across many dimensions other than the additives thought to reduce anxiety. Dogs were used as their own control, with an eventual sample of 28 dogs. Data handling was better within this study with relative homogeneity of the treatment effects observed: of the six outcome measures used, only one parameter showed no effect of treatment (owner – directed aggression). The other five parameters (urinary cortisol: creatinine ratio, stranger directed aggression, stranger-directed fear, non-social fear, and touch sensitivity) were all significantly improved when the dogs were fed the experimental diet. However, inclusion criteria for the study was relatively lax. If a dog scored above 1 on any one question out of circa 28 questions selected from the pre-validated C-BARQ questionnaire for being thought (by the researchers) to be potential measures of anxiety in the dog, they were included in the study. The mean values for each dog on the control diet suggests that dogs were generally scoring low across categories anyway which suggests that, in general these were not necessarily a particularly anxious population of dogs that were studied. Furthermore, the experimental design put the findings at a relatively high risk of bias. Despite the authors having experimental control over the study population, they chose to undertake an experimental design in which all dogs first received the control diet, followed by all dogs receiving the experimental diet. This makes the outcome particularly sensitive to order effects as dogs may simply have improved over time. For example, the cortisol of the dogs was lower at the second visit to the veterinary clinic. This could be because the dog had habituated to the veterinary practice (though the authors point out these dogs visited the vets regularly). Alternatively, if owners chose to participate in a trial testing diets aimed at reducing anxiety, this might alert them to the need to other information that might be used to reduce anxiety in their dogs. Furthermore, the researchers refer to a wash out period of 1 week between trials to ensure that additives have been removed, yet it is not clear what additives they are referring to as the ones in question are only included in the second phase.
In summary, whilst there is some evidence (through a shared direction of effect where a significant effect exists) across the studies that alpha-casozepine may have a clinically beneficial effect in reducing canine anxiety in the medium to longer term, the current evidence is weak and there is a need for good quality, placebo-controlled, randomised clinical trials that specifically address this compound for common anxiety-causing scenarios that this biomolecule may be promoted as a potential solution for.
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