The current study investigates whether chronic pancreatitis pain is accompanied by a decline in cognitive performance, and whether this decline could be related to neurodegenerative properties of the chronic pain. Neuropsychological profiles of patients suffering from chronic pancreatitis pain were compared to those from healthy matched controls.
We found that patients with chronic pancreatitis pain performed significantly worse on tests within all three cognitive domains compared to matched healthy controls. Moreover, the test scores could best be explained when pain duration was included as a second predictor, additional to being a patient or healthy control. Thus, longer pain durations were associated with greater declines in cognitive performance of patients and ‘pain duration’ resulted in larger effect sizes for predicting the test scores on cognitive tasks than ‘group’ did.
Pain duration particularly affects functions in the cluster psychomotor performance. Psychomotor performance strongly relies on the intactness of the frontal lobes. Thus the psychomotor slowing observed in the pancreatitis pain patients may be attributable to alterations of motor- and premotor cortices as well as midbrain structures regulating the general level of arousal (e.g. the thalamus) 
The findings of the current study related to the domain of psychomotor performance may further have been affected by all four covariates investigated. These factors have all previously been associated with a decrease in psychomotor speed 
. In the current study these four factors all offered some additional explanation for the observed decrease in psychomotor performance in the patients, but this appears less substantial than the explanatory effect of pain duration.
Pancreatitis pain patients also showed impairments in executive functions. Significant effects of pain duration were found on tasks that highly depended on mental flexibility (i.e. switching of attention task), self-monitoring abilities (i.e intrusions on word learning) and withholding a response (i.e. verbal interference). Executive functions represent a high, more abstract level of processing, and are mainly supported by the prefrontal cortex 
. Interestingly, Apkarian et al., 
observed a loss of cortical grey matter in patients suffering from chronic pain, especially in the frontal cortices and thalamus. In a subsequent study, a link between decreased grey matter in the prefrontal lobe and a reduced performance on an emotional decision-making task was suggested 
. The observed decline in psychomotor and executive performance observed in our pancreatitis pain patients might thus also be, at least partly, ascribed to a loss of grey matter in the frontal cortices and thalamus.
Memory performance was the least affected cognitive function in patients with chronic pancreatitis. Mild problems with memory functioning have previously been related to depressive symptoms 
. Thus, a mild decline in memory might be related to the increased depression scores found in the patients compared to healthy controls. Although previous studies of patients with chronic pain often have reported memory deficits 
, this domain is only mildly affected within the current study.
Depression, sleep disturbance, use of opioids, and a history of alcohol abuse, are all factors that have been associated with decreased cognitive abilities. Therefore, in the current study these factors were included in the models explaining the observed variance in neuropsychological test data. Indeed, with respect to a number of the tests, these factors did offer additional explanation for the observed cognitive decline in pancreatitis patients. Of these factors, a history of alcohol abuse appeared to be the most prominent factor. However, the effect sizes of a history of alcohol abuse were still modest in comparison with the effect sizes of chronic pain and pain duration (data not shown). This limited effect might be ascribed to the long duration of alcohol abstinence at time of testing in our patients, i.e. at least one year. Indeed, significant recovery has been found within one year of abstinence in most cognitive domains 
. Fein et al. examined cognitive performance in long-term abstinent middle-aged alcoholics and found that abstinent alcoholics performed similarly to controls in all areas of cognitive performance, except for a minor deficit in spatial processing 
In this study a homogenous group of patients was recruited, all having a confirmed diagnosis of pancreatitis. Despite the patients being homogenous in the cause of the pain, it is still difficult to ascribe the observed cognitive deficits to just one underlying cause. This difficulty is not only due to the variation in the duration of their pain disease but also due to comorbidity with depression, sleep disturbances, the high prevalence of a history of alcohol abuse and a current use of opioid medication. However, by applying multivariate multilevel analyses we were able to entangle at least partially the differential influences of these contributing factors.
The uniqueness of this study is that it is the first study to formally assess the cognitive performance of chronic pancreatitis pain patients. Previous studies in this field have focused on other chronic pain patients e.g. low back pain 
and fibromyalgia 
, or mixed pain conditions in patients with chronic non-malignant pain 
. The similar findings of a decline in cognitive performance in these previous studies and those in the present study support the concept that the chronic pain itself is the denominator of cognitive decline and not the associated pathology giving rise to the chronic pain syndrome.
The direct detrimental effect of pain duration on cognitive performance in the present study is a new observation, which has not been reported previously. This negative effect of pain duration on cognitive performance supports the novel concept of viewing chronic pain as a disease with neurodegenerative properties. From a therapeutic perspective, the suggestion that neurodegeneration may be related to chronic pancreatitis pain is extremely relevant. Typically, chronic pancreatitis patients with pain are treated with pain medication including opioids over long periods of time, with limited treatment success and low health-related quality of life, predominantly as a result of persisting or relapsing pain despite medication 
. As a consequence, patients frequently become unemployed, and may even be deprived of the ability to indulge in social and sport activities 
. In this context, earlier and more effective therapeutic interventions targeting not only the cause of pain or blocking sensory input, but also specifically addressing the associated central neuroplasticity might reduce or prevent neurodegeneration and decline in cognitive performance, thereby improving the pain outcomes and quality of life in these patients.