The pain, depression, and fatigue symptom cluster in advanced breast cancer: covariation with the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system.

OBJECTIVE: Neuroendocrine-immune models have been proposed to account for the frequent co-occurrence of pain, depression, and fatigue (PDF) among cancer patients. DESIGN: In a cross-sectional observational study of advanced cancer patients (N = 104), we tested the hypothesis that the PDF cluster covaries with proposed biological mediators: hormones of the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. MAIN OUTCOME MEASURES: PDF symptoms were measured using the Brief Pain Inventory, Fatigue Symptom Inventory, and the Center for Epidemiological Studies Depression scales. HPA activation was indicated by plasma levels of cortisol and adrenocorticotropic hormone, and SNS activation was indicated by plasma epinephrine and norepinephrine. RESULTS: Preliminary analyses supported the use of covariance structure modeling to test whether shared variance among hormone levels predicted shared variance among PDF symptoms. Latent variable analysis indicated that neuroendocrine levels predicted PDF (standardized beta = .23, p = .039), while controlling for important disease and demographic variables. CONCLUSION: Previous studies have linked individual symptoms to individual biomarkers. The observed significant paring of the 4 hormones to the PDF cluster provides the first evidence suggestive of stress hormones as a common mechanism for the co-occurrence of pain, depression, and fatigue symptoms.

The impact of early repeated pain experiences on stress responsiveness and emotionality at maturity in rats.

The intensive care necessary for premature newborns is characterized by multiple procedures, many of which are painful. Given emerging evidence that such early pain during this time of high brain plasticity may affect long-term neurodevelopmental and social-emotional functioning, this study explored the impact of early repeated pain on emotionality and stress responsivity at maturity. From birth through postnatal day 7, Fischer 344 pups underwent either paw needle prick every day versus every other day or daily paw touch, or were left unperturbed. Each paw received the designated perturbation once per day. At maturity, some animals underwent emotionality testing: either a 4-day series of open field exposures or a single elevated plus-maze (EPM) exposure. The paw prick groups exhibited less open field habituation and occupied the EPM open arms more. Two weeks later, all animals were either subjected to forced swim or not. At 1h post-swim, animals underwent either blood withdrawal for plasma corticosterone (CS) levels and ex vivo natural killer cell activity (NKCA) or were injected intravenously with radiolabeled NK-sensitive syngeneic MADB106 tumor cells and assessed for lung tumor retention. Sex was a major factor in the manifestation of perturbation-related differences in the biologic outcomes. Whereas postnatal pain differentially affected baseline tumor retention between males and females, only males exhibited perturbation-related differences in swim stress-induced increases in tumor retention and CS. Finally, male-female differences were evident in CS, NKCA, and tumor responses to swim stress. These findings suggest that early pain affects neurodevelopmental function in the mature organism; however, these relationships are complicated by sex differences, the postnatal pain schedule, and the outcome measured.