Pain and Immunologic Response to Root Canal Treatment and Subsequent Health Outcomes HENRIETTA L. LOGAN,PHD, SUSAN LUTGENDORF,PHD, H. LESTER KIRCHNER,PHD, ERIC M. RIVERA, DDS, MS, AND DAVID LUBAROFF,PHD Objective: This study examined the effects of pain and stress associated with a dental procedure, root canal treatment (RCT), on natural killer cell cytotoxicity (NKCC) and the subsequent development of symptoms of upper respiratory illness during the following month. Methods: Patients (N = 33) were recruited from those scheduled for RCT appointments. Subjects for a non-RCT comparison group (N = 14) were also recruited from dental clinic patients. Peripheral blood was drawn by use of an indwelling catheter three times: just before RCT, 30 minutes after injection of a local anesthetic, and 30 minutes after RCT (a parallel time course was followed for the comparison group.) Blood was assayed for cortisol and NKCC. Subjects completed a health diary in the month after RCT. Results: Patients showed a significant increase in NKCC between baseline and RCT and a significant decrease from RCT to after RCT, whereas the comparison group did not. The NKCC following the RCT was negatively correlated with the pain level during RCT (r =-0.48, p  .01) and pain levels 2 and 6 hours after RCT (r =-0.43, p  .05; r =-0.44 p  .05, respectively). The patient group reported significantly more illness episodes 2 weeks after RCT than the comparison group (Wilcoxon rank sum = 4.78, p = .03). Discriminant function analysis correctly classified 88% of the subjects into the illness category using predictor variables of post-RCT NKCC, stress, and pain levels during RCT (F(3,21) = 8.23, p  .001). Conclusions: Transitory changes in NKCC associated with pain and stress may be implicated in the development of infectious disease episodes after an acute stressful event. Key words: pain, stress, natural killer cell cytotoxicity, health outcomes, dental procedures. IV = intravenous; NK = natural killer cells; NKCC = natural killer cell cytotoxicity; RCT = root canal treat- ment. INTRODUCTION Although there is substantial evidence that acute and chronic stress are associated with changes in im- mune function (1–5), relationships among stress, im- mune changes, and disease outcomes are less clear (6 –9). In addition, there are reported associations be- tween pain and measures of immune function (10, 11), but relationships among pain, immune function, and vulnerability to disease are not well established. Inves- tigation of these relationships is particularly relevant for patients who must undergo painful or stressful medical or dental procedures and who may be vulner- able to complications or negative health outcomes. There is also evidence that stress and vulnerability to illness may be linked (12). We previously found that patients who reported moderate to severe levels of stress during the week before RCT reported signifi- cantly more flu and cold symptoms in the subsequent month (13). The results of these studies suggest a pro- spective relationship between stress and disease outcome. Several attempts have been made to establish im- mune and neuroendocrine mediators linking stress and disease outcomes. One of the most extensively examined immune measures associated with stress and illness is the cytotoxic function of natural killer cells (NKCC) (14 –17). NK cells play an important role in viral surveillance and in the overall defense against viral infections (18, 19). It has been proposed that even limited transitory changes in the immunologic equilib- ria in which NK activity fluctuates in response to psychological stressors may have negative conse- quences for health (20). Most studies have observed downregulation of NK activity in patients under chronic stress, but NK activity seems to be temporarily enhanced during acute stress (21). It is also possible that after an extended acute stressor there is a recovery period during which NK activity drops below some critical level, and this time point may provide a win- dow for disease susceptibility (22). Acute pain usually results in a suppression of NKCC (11, 23), although one study found results to the con- trary. Greisen et al. (24) reported a slight increase in NKCC in response to painful electric stimulation. The increase in NKCC was blocked when local anesthetic was applied before painful stimulation. Unmanaged surgical pain also leads to suppression of NK cell activity, which seems to mediate the surgery-induced enhancement of metastatic colonization of tumor cells in rats (25). Whether and to what extent such acute From the Division of Public Health Services and Research (H.L.L.), University of Florida, Gainesville, Florida; Departments of Psychol- ogy (S.L.), Endodontics (E.M.R.), and Urology and Microbiology (D.L.), University of Iowa, Iowa City, Iowa; and Department of Pe- diatrics (H.L.K.), Case Western Reserve University, Cleveland, Ohio. Address reprint requests to: Henrietta Logan, PhD, Box 100404, 1600 SW Archer Rd., D8-39, Public Health Services and Research, University of Florida, Gainesville, FL 32610. Email: hlogan@dental.ufl.edu Received for publication March 16, 2000; revision received Octo- ber 11, 2000. 453 Psychosomatic Medicine 63:453– 462 (2001) 0033-3174/01/6303-0453 Copyright © 2001 by the American Psychosomatic Society