From Animal Data to Human Practice

Naturally Occurring Model of Treatment

In cats with FIC, laboratory studies have revealed that environmental enrichment was associated not only with reduction in LUT signs, but with normalization of circulating catecholamine concentrations, bladder permeability, cardiac function [89,90], and reduced responses to acoustic startle[41]. We also conducted a ten-month prospective observational study of client-owned cats with moderate to severe FIC[10]. In addition to their usual care, clients were offered individualized recommendations for multimodal environmental modification based on a detailed environmental history obtained from the owner. In addition to significant reductions in LUT signs, decreased fearfulness, nervousness, signs referable to the respiratory tract, and a trend toward reduced fear-like behaviors were identified.

We have also observed sickness behaviors after environmental enrichment, both in healthy cats and in cats with FIC, in response to unusual external events[73]. Sickness behaviors refer to a group of nonspecific clinical and behavioral signs and symptoms that include variable combinations of vomiting, diarrhea, anorexia or decreased food and water intake, fever, lethargy, somnolence, enhanced pain-like behaviors, decreased general activity, body-care activities, and social interactions[23]. These behaviors are well-documented physiologic and behavioral responses to infection found in all species studied, and also occur in response to aversive environmental events[54]. Psychological stressors recently have been linked to immune activation and pro-inflammatory cytokine release[67] as well as to changes in mood and pathological pain[75]. Thus, sickness behaviors can result both from activation of either peripheral (e.g., infection) or central (e.g., psychological) pathways, or both.

Increasing age and weeks when unusual external events occurred, but not disease status, resulted in a significant increase in total sickness behaviors observed in the cats when controlled for other factors. Unusual external events were associated with significantly increased risks for decreases in food intake and elimination, increases in defecation and urination outside the litter box. These results suggest that some of the abnormalities observed in cats with FIC may represent amplifications of responses observed in healthy animals, possibly due to differences in genetics, early life experience, or disease chronicity, as appears to be the case in humans with BPS/IC and other chronic abdominal and pelvic pain syndromes[18].

Warren et al. [85], recently suggested three hypotheses about the causes of BPS/IC that accommodate the presence of multiple systemic symptoms in these patients: (1) that BPS/IC initiates a pathophysiology that results in other disorders, (2) that these disorders initiate a pathophysiology that results in other disorders and in BPS/IC, and (3) that a preceding pathophysiology results in both. One way to exclude one or more of these hypotheses would be a to conduct a prospective longitudinal study of healthy individuals. Another would be to treat patients with BPS/IC to determine the effect on their systemic symptoms. If other symptoms remained in recovered patients, hypothesis 1 would be excluded, if other symptoms were treated and BPS/IC remained, hypothesis 2 would be excluded, and if a hypothesized underlying pathology was treated and BPS/IC remained, hypothesis 3 would be excluded.

Effective environmental enrichment might be conceptualized as one treatment approach to test these hypotheses. What we have found in both in cage-confined and client-owned cats with FIC is that enrichment results in statistically and clinically significant improvements in all disease signs, arguing against exclusion of hypothesis 3. The fact that these improvements occurred in the absence of any treatment directed at the bladder or any other peripheral organ provides evidence for exclusion of hypotheses 1 and 2. I await comparable studies in human beings with BPS/IC to determine the extent to which these results are predictive of responses in them.

PRACTICAL IMPLICATIONS

Animal models appear to have made relatively few documentable contributions to drugs that can be used in practical situations by clinicians treating patients with chronic abdominal and pelvic pain syndromes, or for any other chronic pain condition for that matter[30]. In contrast, environmental enrichment has resulted in statistically and clinically significant improvements in both a chronic induced model and a naturally occurring model of neuropathic pain, one of which serves as a model for BPS/IC.

But what does environmental enrichment mean for clinicians? One significant difference between human and non-human animals is their level of consciousness. While animals may be said to have primary consciousness to varying degrees, only humans appear to have secondary consciousness – understanding the potential meaning of symptoms for their personal, social and financial futures. This knowledge can be a double-edged sword. On the one hand, as natural and understandable as it is, ruminating and catastrophizing about one’s pain can exacerbate it[31,35]. On the other hand, effective doctor-patient communications [16,19], empathy[53] and cognitive behavioral therapy[48] may reduce pain and other symptoms in patients with chronic medically unexplained syndromes, and might be conceptualized as “environmental enrichment”. While cognitive and emotional control are disrupted in chronic pain patients, [15] recent studies of cognitive behavioral therapy have shown that multiple functional somatic symptoms improve with effective therapy [70], as has been found for environmental enrichment for cats.

LOOKING AT THE FUTURE

To return to the blind men and the elephant, stories differ in how violent the conflict between the differing perspectives becomes, and how (or if) the conflicts are resolved. In some versions, they stop talking, reminding one of Max Plank’s observation that “…a new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.” In other versions, they start listening and collaborating with each other so that all can eventually “see” the full elephant – the choice is ours.

TAKE HOME MESSAGES

The most important things I have learned from the study of BPS/IC in both cats and people that may be pertinent to other chronic abdominal and pelvic pain syndromes are:

• These are complex syndromes; current evidence suggests to me that BPS/IC is more likely to be a syndrome affecting the bladder than a bladder disease in most cases. If this is the case, urologists, as acute care-focused subspecialty surgeons, are more suited to the diagnosis of BPS/IC than the ongoing care of patients with a chronic medical syndrome. Perseverative efforts to force the disease back into the bladder seem unlikely to succeed.

• Although animal models have provided a wealth of basic scientific information about abdominal and pelvic organ responses to a range of noxious stimuli, these models were based on the presumption that the diseases modeled arose in the organ for which they were named; this no longer seems to be the case for many patients with BPS/IC. One hopes that collaboration among investigators with interest in different organs or processes will permit more thorough evaluation of ecologically relevant models of stress and disease. Such investigations could simultaneously accelerate acquisition of knowledge and reduce the number of animals subjected to these noxious procedures.

• Novel therapies may become more available based on classification of these disorders as central sensitivity syndromes as appropriate. These may include pharmacological agents that modulate gene expression [74,79], as well as online and coaching-based self-management – if evidence for their effectiveness can be demonstrated.

FURTHER READING

Books

Pain in women; A Clinical Guide. New York: Springer; 2013.

Bladder Pain Syndrome A Guide for Clinicians. New York: Springer; 2013.

Smith’s Patient-Centered Interviewing – an evidence-based method.

Review articles

Franklin TB, Saab BJ, Mansuy IM. Neural mechanisms of stress resilience and vulnerability. Neuron. Sep 6 2012;75(5):747–761.

Larauche M, Mulak A, Tache Y. Stress and visceral pain: From animal models to clinical therapies. Experimental Neurology. Jan 2012;233(1):49–67.

Mayer EA, Tillisch K. The brain-gut axis in abdominal pain syndromes. Annual review of medicine. 2011;62:381–396.

REFERENCES

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3. Anda RF, Felitti VJ, Bremner JD, et al. The enduring effects of abuse and related adverse experiences in childhood – A convergence of evidence from neurobiology and epidemiology. Eur Arch Psyc Clin Neurosci 2006;256(3):174–186.

4. Bale TL, Baram TZ, Brown AS, et al. Early Life Programming and Neurodevelopmental Disorders. Biolog Psych 2010;68(4):314–319.

5. Baranowski AP, Abrams P, Berger RE, et al. Urogenital pain–time to accept a new approach to phenotyping and, as a consequence, management. Eur Urol 2008;53(1):33–36.

6. Bjorling DE, Jerde TJ, Zine MJ, et al. Mast cells mediate the severity of experimental cystitis in mice. J Urol 1999;162(1):231–236.

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