A preliminary report on pain thresholds in bulimia nervosa during a bulimic episode

A Preliminary Report on Pain Thresholds in Bulimia Nervosa During a Bulimic Episode Nancy C. Raymond, Elke D. Eckert, Michelle Hamalainen, Diane Evanson, Paul D. Thuras, Boyd K. Hartman, and Patricia L. Faris Subjects with bulimia nervosa (BN) have been shown to exhibit abnormal satiety responses. Short-term satiety is largely mediated by afferent vagal activity. Activation of afferent vagal fibers has also been found to stimulate a descending pain inhibitory pathway that leads to elevation in somatosensory pain thresholds. Therefore, the study of pain thresholds in BN subjects may lead to a better understanding of afferent vagal function in this disorder. In this preliminary study, pressure pain thresholds were assessed in nine

subjects with BN on 3 consecutive days during a binge-eating and vomiting (B/V) episode, during a normal meal, and after an overnight fast. A significant time versus condition effect was found with a significant change in the pain threshold in BN subjects under the B/V condition only. These data are consistent with the hypothesis that vagal afferent activation by a B/V episode also activates the descending pain inhibitory pathway. Copyright © 1999 by W.B. Saunders Company

UBJECTS WITH BULIMIA NERVOSA (BN), by definition, have eating binges in which they consume "an amount of food that is definitely larger than what most people would eat during a similar period of time and under similar circumstances." 1 During eating binges, BN patients have a subjective sense that they cannot "control what or how much" they are eating. 1 They often report that they do not feel full in response to a normal meal 2 and have abnormal patterns of hunger and satiety during ingestion of a meal) Short-term satiety (meal termination) is primarily mediated by vagal afferent nerve activation during the preabsorptive phase of meal acquisition. 4-7 Faris et al. 8 suggested that a key component of the pathophysiology of BN may be a disturbance in short-term satiety mechanisms. Furthermore, we have previously hypothesized that "if BN involves abnormalities in vagal control of short-term satiety, then it may also be accompanied by decreased nociceptive responsivity. ''s This hypothesis was based largely on the studies by Randich et al.,9-12 who have demonstrated in the laboratory rat that vagal afferent stimulation also activates a descending pain inhibitory pathway that modulates incoming somatosensory information. Indeed, our group and others have reported that randomly measured pain detection thresholds (PDTs) are statistically elevated in a BN group compared with a matched population when both pressure 8,13 and thermaP TM nociceptive modalities are evaluated. Additionally, data collected by our group suggest that this elevation may not be a tonic feature of the disorder but instead fluctuates dynamically between bulimic episodes. Two lines of evidence indicate that phasic changes in the PDT are present in individuals with

BN. First, the PDT has been found to correlate positively with the time since the last binge-eating/ vomiting (B/V) episode. 15,16These dynamic fluctuations in pain detection were abolished by ondensatron treatment, a serotonin 3 receptor (5-HT3) antagonist known to reduce vagal neurotransmission. 15,16 From these correlative data, it follows that individuals who binge-eat and vomit more frequently are statistically more likely to be tested shortly after an episode, and are therefore more likely to be tested at the nadir of the PDT. In fact, we have found that randomly measured PDTs are negatively correlated with the number of bulimic episodes per week. 17,1s The purpose of the current study is to examine whether the PDT fluctuates acutely during a B/V episode. Eating a large quantity of food causes a marked distention of the stomach that increases afferent vagal activity/Additionally, vomiting also causes strong stimulation of vagal afferent fibers. 19,2° If changes in afferent vagal activity affect pain thresholds, as already suggested, then pain thresholds should increase after a B/V episode. In

S

From the Department of Psychiatry and Psychiatry Department, Division of Neurosciences, University of Minnesota Medical School, Minneapolis, MN. Supported by grants from the Minnesota Medical Foundation, Grant No. MO1RROO4OOfrom the National Center for Research Resources, General Clinical Research Center Program, Grant No. 5RO1MH49385 from the National Institute of Mental Health, and Grant No. 5RO1DK52291-04 from the National Institute of Diabetes and Digestive and Kidney Diseases. Address reprint requests to Nancy C. Raymond, M.D., Department of Psychiatry, University of Minnesota, Box 393 Mayo, 420 Delaware St SE, Minneapolis, MN 55455. Copyright © 1999 by W.B. Saunders Company 0010-440X/99/4003-000651 O.00/0

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this study, comparisons were made between pain thresholds under a B/V condition, a fasting condition, and a normal meal condition in BN subjects. Based on research by Faris et al. 8,15,16 and Ren et al., 9 we predicted that the PDT would increase after a B/V episode due to vagal stimulation and then PDT would subsequently decline. METHOD

Subjects Nine BN subjects were recruited by a newspaper advertisement for volunteers with BN who were interested in a research study of sensory perception. The subjects were women aged 18 to 40 years, free of medical conditions that would affect pain thresholds, and medically stable at the time of entry into the study. All subjects met DSM-III-R 21 criteria for BN and used vomiting as a compensatory response to their binge-eating behavior. None of the subjects had a regular pattern of laxative abuse in the previous 6 months. Additionally, BN subjects had a minimum of three B/V episodes per week for 6 months prior to the study. Exclusion criteria included active suicidal ideation, a diagnosis of schizophrenia or bipolar disorder, a substance use disorder in the prior 6 months, or the use of psychoactive medication or chronic use of pain medication during the 6 weeks prior to testing. All subjects had to be in their normal weight range (within 15% of ideal body weight for height, Metropolitan Life Tables, 1954).

Pressure Pain Testing Procedure Mechanical (pressure) pain thresholds were measured using a Ugo Basili analgesiometer (Milan, Italy). This device applies an increasing amount of pressure (0 to 1,040 g at a rate of 64 g per second) to the center of the ventral surface of the phalanx. The subject's finger rests on a 1-mm2 plastic tip located on top of a load cell for direct input of pressure data into a Macintosh Quadra 800 computer with Superscope II software (G.W. Instruments, Somerville, MA). The equipment records the pressure exerted on the finger and the time the subject presses a microswitch (see below). Testing was conducted in the subject's room on the General Clinical Research Center (CRC) inpatient ward. The patient was seated comfortably in a recliner or semireclined in bed throughout the testing procedure. Standardized instructions were read to the patient. Subjects were told that the testing could be terminated at any point upon their request and that they should keep their eyes closed throughout the entire procedure. The tester placed the four fingers of the nondominant hand on the tip of the analgesiometer in succession, starting with the little finger. The subject held a microswitch in her dominant hand and was instructed to push the microswitch when the pressure first became painful (PDT), and to push the switch a second time when the pain became too uncomfortable to continue (pain tolerance threshold [PTT]). After the subject pushed the microswitch the second time, the apparatus was immediately lifted off of the subject's finger, terminating the test on that finger.

Protocol All subjects signed a consent form approved by the University of Minnesota Institutional Review Board prior to entering

the study. All subjects were assessed using the Structured Clinical Interview for DSM-III-R. 22 A physical examination with an emphasis on neurologic evaluation was performed. Analyses of electrolytes, blood urea nitrogen, creatinine, and glucose, liver function tests and a complete blood cell count were completed on all subjects to guarantee that they were medically stable prior to entry into the study. During the initial evaluation, subjects were interviewed by a dietitian and completed a food-frequency questionnaire that was analyzed using the National Cancer Institute's HHQ-Dietsys Analysis Software (National Institute of Cancer, 1993). The food-frequency questionnaire and the CRC dietitian's clinical interview were used to assess the foods typically ingested by each BN subject during their binge-eating episodes. These foods were later provided to the subjects for the binge-eating episodes that were part of the study. Subjects were admitted to the CRC inpatient ward on the night before initiation of the study. Subjects were told prior to admission that they would only be allowed to eat food provided for them while on the CRC ward and that they were not to participate in binge-eating unless directed to do so by the research staff. The subjects' and any visitors' belongings were searched to ensure that they did not bring food to the unit. The staff stayed with the subjects for 1 hour after ingestion of the nonbinge meals to reduce the risk of purging. Subjects received nothing by mouth after an optional evening snack on the night of admission. All subjects practiced the pain testing procedure one time on the dominant hand prior to admission or on the night of admission. On the first day of data collection, BN subjects were asked to have a B/V episode on the inpatient unit. Baseline pain testing was performed at 8:30 and 9:00 AM. At 9:15, the subject's binge foods were brought in by the CRC kitchen staff. The subject was left alone to binge-eat. Subjects were told to binge-eat as long as they wanted to and then to signal the research assistant, who immediately entered the room and conducted the pain testing. The subject was then allowed to vomit in private for as long as they chose, and again signaled the research assistant at the end of the vomiting episode to repeat the pain testing. All vomitus was collected and measured. Pain testing was also performed 1 hour after the B/V episode was completed. On days 2 and 3 of the protocol, subjects were randomly assigned to one of two conditions. Under the fasting condition, subjects fasted during the time of their B/V episode under the B/V condition. Studies in animals have indicated an increase in the pain threshold as a result of food deprivation. 23-25Thus, the fasting condition controlled for the possibility that changes in the pain threshold during the B/V condition were caused by the subjects' completely emptying their stomachs when vomiting. If they vomited the stomach contents before any absorption occurred, then, from a physiological perspective, they were essentially fasting on the B/V day. Under the meal condition, subjects were provided with a balanced breakfast meal (400 calories, 30% fat, 20% protein, and 50% carbohydrate) to eat during the time they had their binge-eating episode under the B/V condition. The meal condition controlled for the effect of food intake on the pain threshold during the B/V condition. All food and caloric liquids ingested over the course of the study were recorded, and caloric content was calculated by the CRC dietary staff. Under the meal and fasting conditions, pain testing

PAIN THRESHOLDS iN BULIMIA NERVOSA

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was performed on the same time schedule as the testing on the B/V day.

Data Analysis The baseline PDT and PTT were calculated by averaging the two baseline testing sessions. The four time points used in the analysis were the baseline test, the test immediately after the binge eating episode (posthinge), the test immediately after the vomiting episode (postvomit), and the test 1 hour after the vomiting episode (1 hour postvomit) under the B/V condition. The equivalent time points under the meal and fasting conditions were used in the analysis. The mean PDT and PTI? values were derived from the average PDT and PTT for the four fingers on the nondominant hand. The criteria for significance in all analyses was P less than .05. To test for differences between the three conditions in BN subjects, a three (conditions) × four (time) repeated-measures multiple analysis of variance (MANOVA) was performed with PDT as the dependent variable. Further comparisons of individual time points within the B/V condition and between the same time points over different conditions in BN subjects were made using matched-pairs t tests. By definition, the PTT cannot be reported until the subject has reported the PDT. To test for changes in the PTT between conditions in BN subjects independent of changes in the PDT, a three (conditions) x four (time) repeated-measures MANCOVA with PTT as the dependent variable and PDT as a covariate was performed.

RESULTS

The mean age of the nine BN subjects was 24 _ 7 years. The mean body mass index was 21.0 _+ 1.2 kg/m 2. Subjects reported a mean of 9.2 +_ 7.4 (mean +_ SD) binge episodes (range, three to 28) and 10.0 + 9.2 vomiting episodes (range, four to

38) the week before the test. The mean calories consumed during a binge was 2,632 +_ 1,172, with a range of 965 to 4,060. The mean volume of vomitus was 2,098 _+ 1,833 mL, with a range of 100 to 6,500. The mean group score on the Beck Depression Inventory26was 10.2 + 6.8. The Hamilton Depression 27 and Anxiety Rating Scale 28 scores were 10.1 + 5.8 and 9.2 -+ 4.1, respectively. Two subjects met criteria for major depressive disorder, and one subject met criteria for social phobia. Regression analysis did not show a significant correlation between depression and anxiety symptoms and the baseline pain threshold or the degree of change in the pain threshold. This result is consistent with our previous reports in which depression did not correlate with the PDT. 8,16 The repeated-measures MANOVA in BN subjects with PDT as the dependent variable showed a significant time versus condition effect (F(6,48) = 3.10, P < .012; Fig 1 and Table 1). In the B/V condition, there was a significant decrease in the PDT between the immediate postvomit measure and the 1-hour postvomit measure (t(1,8) = 3.67, P = .006). The PDT did not increase significantly between the baseline test and the immediate postvomit test ( t ( 1 , 8 ) = 1.65, P = . 138). However, the immediate postvomit measure on the B/V day was significantly elevated compared with the measurement taken at an equivalent time point in the protocol under the meal

475 -

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.~- 400Fig 1. Mean PDT for 9 BN subjects tested under 3 conditions (binge-vomit, meal, fast) over 4 time points (baseline, postbinge, immediately postvomit, 1-hour postvomit) (F(6,48) = 3.10, P < .012); ttests were used to compare specific data points as follows (letters indicate points compared): (a) t(1,8) = 3.67, P = .006; (b) t(1,8) -2.89, P = .02; (c) t(1,8) = 2.54, P = .035.

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RAYMOND ET AL

Table 1. Mean PDT (grams, mean _+ SD) in Nine BN Subjects Tested Under Three Conditions (binge-vomit, meal, and fast) Over Four Time Points (baseline, postbinge, immediately postvomit, and 1-hour postvomit) Parameter Baseline

Binge-VomitDay

Meal Day

Fast Day

384.0 _+ 138.9 385.1 -+ 202.3 363.1 _+ 183.6

Postbinge

410.1 -4- 161.6 369.6 _~ 190.7 366.3 _+ 194.1

Postvomit

450.4 _+ 227.4

1 h postvomit

365.3 + 189.7 388.5 -+ 240.8 386.8 _+ 196.1

369.8 _+ 207.2 391.0 + 231.6

condition (t(1,8) = 2.89, P = .020) and the fasting condition (t(1,8)= 2.54, P = .035). Across the three conditions, the PDT did not differ significantly at any other time points. There were no changes in the PDT after a normal meal or under the fasting condition. A similar pattern of results was observed for the PTT in the B/V condition. However, when the PDT was entered as a covariate, changes in the PTT were no longer significant. Therefore, the ability to tolerate additional pain after the pressure is first perceived as painful does not change across a B/V episode. DISCUSSION

Based on the study by Randich et al., H we hypothesized that the PDT would increase after the B/V episode due to acute stimulation of the gastric vagus nerve and then subsequently decline. The MANOVA showed significant changes over time related to an apparent elevation on the B/V day at the immediate postvomit time point and a subsequent significant decline between that time point and the 1-hour postvomit time point. Thus, these preliminary data provide the first direct evidence for acute modulation of pain detection by bulimiclike behaviors. The data are consistent with the hypothesis that vagal afferent activation activates the descending somatosensory inhibitory pathway. 9 We have previously acknowledged that the PDT should not be expected to be a pathognomonic

finding for BN. Indeed, abnormal pain thresholds have been reported in several other psychiatric populations, z%35 However, previous attempts to correlate the PDT with other psychiatric and physiologic variables have provided little insight into the variables that control the PDT in this population. 8'13'14'16'36'37 TO the best of our knowledge, the data presented here offer the first direct demonstration that pain thresholds are acutely modulated by bulimic behaviors. Perhaps due to the small sample size, we did not find correlations between the caloric content and the PDT or between the volume of vomitus and the PDT. Additionally, we did not have a good means to assess the changes in mood that can occur during a B/V episode 38,39that could affect pain perception. However, if the change in mood affected pain detection, we would have expected also to observe an elevation in pain tolerance. The present preliminary data are consistent with the previous correlative data (discussed in the introduction) in two important ways. First, the data indicate that PDTs are at a nadir within 1 hour after a B/V episode. Second, the data are consistent with the theory that the acute normalization of a physiological process (i.e., vagal activity) by pathological behaviors (bingeing/vomiting) provides a biological mechanism by which the bulimic behaviors are positively reinforced. 15,16A replication of this study with a larger sample size and studies in which individual patients are evaluated across multiple spontaneously occurring B/V episodes before and during ondansetron treatment are warranted to further test the hypothesis that vagal dystonia is involved in "driving" and "reinforcing" bulimic behaviors. ACKNOWLEDGMENT The authors would like to acknowledge Don Simone, Ph.D., for expertise regarding the pain threshold testing procedure.

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