Altered Rectal Perception Is a Biological Marker of Patients With Irritable Bowel Syndrome

Transcription

1 GASTRONTROLOGY 1995;109:40-52 Altered Rectal Perception Is a Biological Marker of Patients With Irritable Bowel Syndrome HOWARD MRTZ,* BRUC NALIBOFF, *' JULI MUNAKATA,* NGAR NIAZI,* and MRAN A. MAYR* VA/UCLA CUR:Gastroenteric Biolog~ Center/Neuroenteric Biology Group, Departments of *Medicine and *Psychiatry, UCLA and West Los Angeles VA Medical Center, Los Angeles; and ~VA Sepulveda Medical Center, Sepulveda, California Background & Aims: Lowered visceral perception thresholds have been suggested as a biological marker of irritable bowel syndrome (IBS). The current study sought to determine the prevalence of altered rectal visceral perception in patients with IBS and the correlation of altered perception thresholds with subjective symptoms. Methods: Anorectal manometry and rectal perception thresholds to balloon distention were determined in 100 patients with IBS and 15 control subjects. Gastrointestinal and psychological symptoms were assessed by questionnaire. Perception thresholds and symptoms were reassessed after 3 months in 15 patients with IBS. Results: Ninety-four percent of patients showed altered rectal perception in the form of lowered thresholds for aversive sensations (discomfort), increased intensity of sensations, or altered viscerosomatic referral. Hypersensitivity was found only for aversive sensations in response to rapid phasic distention; stool thresholds and thresholds in response to slow ramp distention were normal. Cluster analysis by physiological parameters identified three IBS subgroups with predominant patterns of symptoms. Longitudinal evaluation indicated a correlation between changes in perception thresholds and symptom severity. Conclusions: Because altered rectal perception is present in almost all patients with IBS and perception thresholds correlate with temporal changes in retrospective symptom severity, altered rectal perception represents a reliable biological marker of IBS. B ecause of the lack of specific and reliable biological markers, attempts to classify patients with irritable bowel syndrome (IBS), monitor symptom severity, and evaluate the response to therapy have been limited to the assessment of subjective symptom reports. 1 A biological marker could either be an invariable trait of IBS, persisting despite variations in symptom severity, or represent a variable state, its quality and intensity fluctuating in accordance with symptom severity. Previously proposed biological markers, such as differences in colonic slow wave frequency, 2 alterations in the gastrocolonic motor response, 3 and altered intestinal motor patterns, 4 are nonspecific and/or do not show an accurate correlation with subjective symptoms. Several laboratories have suggested that lowered sensory threshold to rectosigmoid balloon distention is a reproducible marker of IBS 5 7 and that lowered visceral perception thresholds may be a surrogate marker for chronic visceral hyperalgesia in patients with IBS. 8 Furthermore, such common IBS symptoms as the sensation of incomplete rectal evacuation, urgency, and lower abdominal pain may be the subjective equivalent of altered visceral sensations. 9'~ However, Prior et al. found that only 58% of patients with IBS showed lower rectal volume thresholds to rapid balloon distention, 6 and other studies have not assessed large numbers of patients or reported the prevalence of rectosigmoid hypersensitivity. In the current study, we evaluated altered rectal perception as a biological marker of IBS. To do so, we sought to answer five questions by correlating self-reported subjective symptoms, rectal perception, and viscerosomatic referral patterns during the initial evaluation and following these parameters for 3 months. (1) What is the prevalence and nature of altered rectal perception in a large number of patients with IBS? (2) Do subjective symptoms correlate with sensory thresholds for stool and discomfort? (3) Are there distinct empirically defined subgroups of patients with IBS who have different biological characteristics? (4) Do anal reflexes and physiology correlate with rectal perception thresholds and symptoms? (5) Do rectal sensory thresholds of patients with IBS change during a 3-month period and, if so, is a change in thresholds paralleled by a change in self-reported symptoms? We found that nearly all patients with IBS show altered rectal perception and that this alteration correlates with certain IBS symptoms. We identified three sub- Abbreviations used in this paper: IBS, irritable bowel syndrome; VAS, visual analog scale by the American Gastroenterological Association /95/$3.00

2 July 1995 RCTAL HYPRALGSIA IN IBS 41 groups of patients with IBS based on physiological vari- ables. Finally, changes in retrospective evaluation of symptom severity over time correlate with changes in perceptual threshold. Some of these results have been reported previously in abstract form/ Materials and Methods Subjects Normal controls. Seven female and 8 male normal subjects (mean age, 37 years; range, years) were recruited by advertisement. None of the subjects had any evidence (by history or physical examination) of an acute or chronic illness. In particular, there was no evidence for a chronic pain syndrome or for abdominal symptoms either by bowel symptom questionnaire or by personal history. Results from these subjects were used to establish 95% confidence intervals for perception thresholds and rectal compliance. Patients with IBS. Anorectal sensory and motor function was evaluated in 100 consecutive patients (69 female and 31 male between 1992 and 1993) from the UCLA Center for Functional Bowel Disorders and Abdominal Pain. The mean age was 44 years (range, years) A diagnosis of IBS was made using the ROM criteria, " 1 exclusion of organic disease, and the diagnosis of a gastroenterologist experienced in the evaluation of patients with functional bowel. Patients were classified into a low-threshold IBS group (n = 61) when their respective perception threshold for discomfort during the phasic distention protocol (expressed as pressure or wail tension) was below the 95% confidence interval of the mean threshold of the group of 15 healthy volunteers. Patients' predominant bowel habit was classified as diarrhea-predominant, constipation-predominant, or alternating according to bowel habits reported in the modified Talley bowel symptom 11 quesnonnalre. The clinical characteristics of patients, including predominant bowel habit and abdominal symptoms, are summarized in Table 1. Informed consent was obtained from each subject Questionnaires Bowel symptom questionnaire, At the time of their first encounter at the UCLA functional bowel clinic, patients completed a detailed questionnaire regarding their bowel habits, abdominal symptoms, and quality of life. The questionnaire is the previously validated Talley bowel symptom questionnaire 1~ with nine additional questions designed to assess quality of life and additional measures of bowel function and abdominal pain. We analyzed 41 questions that included 6 on type of IBS symptoms (Manning criteria) and 1 on severity, 9 indicating various types of chest and abdominal discomfort, 5 characterizing constipation, 1 characterizing diarrhea, and 3 describing bowel habits. Four questions rated quality of life, and 3 rated disease severity using a visual analog scale (VAS). VAS ratings of disease severity have recently been shown to correlate well with patient and physician ratings of IBS sever- Table 1. Bowel Symptoms and Rectal Sensitivity in IBS Symptoms All IBS Lowthreshold IBS Normalthreshold IBS Diarrhea (%) ~ 5 Constipation (%) Alternating (%) Rectal fullness (%) ~ 28 Frequent urge (%) a 0 Abdominal distention (%) Cramps with bowel movement (%) Relief with bowel movement (%) Incomplete evacuation (%) Mucus per rectum (%) Primary symptoms ap < 0.05 for comparison of low-threshold IBS and normal-threshold IBS. 17 lty. - Because anorectal testing was performed up to 2 weeks after the initial bowel symptom questionnaire was administered, 2 questions about acute flare-ups in symptoms (within 24 hours and within 2 weeks) were asked at the time of the test. Patients were also asked to draw the area of their discomfort on an anterior and posterior body map at the time of the original evaluation. Follow-up questionnaire. A group of 15 patients who were willing to undergo repeated rectal sensory testing were reexamined 3 months after the initial testing. These studies were performed to determine whether changes in perception thresholds are reflected in perceived symptom severity To obtain the most general correlation, no attempt was made to standardize the patient population or the type of therapeutic intervention. Patients were followed up by different center physicians and received a variety of therapies, including relaxation training, low-dose amitriptyline (50 mg/day or less), and Metamucil (Procter and Gamble, Norwich, NY) between their first and second tests. They completed a questionnaire at the time of the second manometry assessing retrospective changes in symptom severity. Because the rating of abdominal pain seems to be a good marker for IBS symptom severity, 12 we analyzed two questions from the questionnaire that asked patients to rate the amount of abdominal pain and abdominal discomfort (bloating and gas sensation) they experienced If abdominal pain was part of the initial problem, change in pain was compared with the threshold change If abdominal pain was not a symptom, then change in abdominal discomfort (bloating or gas) was compared with the threshold change. Both questions were scored by patients on a VAS ranging from worse (-5) to unchanged (0) to resolved (+3). The change in sensory threshold was compared with the retrospective change in the IBS symptoms listed above. ven though the retrospective assessment of change in symptom severity may be subject 13 to memory biases, it represents the most common way by which IBS symptom changes are assessed in clinical practice.

3 42 MRTZ T AL. GASTRONTROLOGY Vol. 109, No. 1 Psychological symptom questionnaire. Patients completed the SCL-90 psychological symptom questionnaire, which assesses symptom severity in the following areas: anxiety, depression., hostility, interpersonal sensitivity, obsessivecompulsive behavior, paranoia, phobic behavior, psychosis, and somatization. 14 Scores are recorded on a scale, on which any score of 63 or greater is abnormal compared with normal control subjects. quipment Volume-displacement device. A computer-driven vol- ume-displacement device (Synectics Visceral Stimulator; Synectics, Stockholm, Sweden) was used to inflate a balloon either continuously at a constant volume rate of 40 ml (ramp distention) or rapidly to constant pressure plateaus (phasic distention). During phasic distention, semirandomly ascending pressure pulses (15, 10, 25, 20, 35, 30, 45, 40, 55, and 50 mm I-Ig) 15 of 30 seconds' duration were separated by 30-second intervals at the resting pressure of 3 mm Hg. The distention device, which records pressures and volumes simultaneously (sampling rate of 1 per second) was connected to a subject-operated marker device that logs the sensations of stool or discomfort onto the data file as balloon inflation occurs. 15 When a subject triggered the marker for pain during phasic or ramp distention, the device instantaneously deflated. There was a fixed pressure limit that also triggered balloon deflation for pressures >60 mm Hg or volumes >400 m. Curve fitting using a cubic polynomial was performed for the ramp distentions using the Sigmaplot software (Jandel Scientific, San Rafael, CA) as previously described) 5 Dynamic compliance (dv/dp) was calculated by taking the derivative of the curve. Static compliance was calculated by solving for pressure at the desired volume and dividing volume by pressure. The curve inflection point was taken as another measure of compliance. The inflection point is the volume at which the second derivative of the curve is zero (see Figure 1). It has been suggested that the flat portion of the curve reflects a high-compliance zone resulting from activation of receptive relaxation reflexes in response to distention. I6 The inflection point would therefore be expected to estimate the degree of receptive relaxation and indirectly the static compliance at higher distention volumes. The inflection point correlated significantly with static compliance at 200 m (r = 0.44; P < 0.005). A latex balloon was attached to a silastic tube (external diameter, 18F) and tied at both proximal and distal ends to prevent longitudinal expansion of the balloon during inflation (MAK-LA, Los Angeles, CA). The distance between the two attachment sites was 11 cm. Distention to a maximal volume of 400 ml resulted in a spherical balloon shape. The absence of longitudinal expansion was validated by inflating the balloon inside a glass cylinder with a diameter of 10 cm. The balloon was inflated repeatedly before use to rule out any leak and to measure its intrinsic compliance. In preliminary studies, it was found that during the initial three balloon inflations, 60 I I I I I 50 A -I- o~ 4O "~ 30 M ID.o 20 IQ point I I J J J Rectal Volume (ml) 250 Figure 1. Rectal compliance curve. A representative rectal compliance curve with an initial flat portion and a second steeper portion is shown. The polynomial curve was fit to data as described in Materials and Methods. The inflection point is indicated on the flat part of the curve where the second derivative of the polynomial becomes O. the maximally reached balloon pressure decreased by 10%. After this initial decrease, the volume-pressure relationship of the balloon remained constant during subsequent inflations. For determining sensory thresholds to distentions, balloon pressures at each volume were automatically subtracted from rectal pressures by the barostat software. The balloons were tested again after completion of each experiment to ensure there was no leak or change in compliance with repeated inflation. The lubricated balloon was inserted into the rectum so that the distal attachment site was 4 cm from the anal verge. The tube was then secured in its proper position with tape. Anorectal manometry. Anal canal pressures during phasic distention were monitored using a multilumen waterperfused catheter (Arndorfer Instruments, Greendale, WI) and a Synectics polygraph (Irving, TX) as previously described. 15 Resting, stimulated, and defecation anal pressures were measured. Stimulated anal pressures were measured in the anal canal as a second nonperfused catheter was pulled through at the rate 0.1 cm/s to create an anal shear force stimulus. This type of stimulus has been shown in animals to be a powerful stimulus for the activation of anal afferents involved in reflex contraction of the external and internal anal sphincters Paradoxical anal sphincter contraction was defined as an increase in pressure above baseline with defecation efforts. The pressure at which progressive rectal distention (during the phasic distention protocol) triggered internal and sphincter relaxation (anorectal inhibitory reflex) was recorded. We defined internal anal sphincter relaxation as a reduction of pressure from baseline of at least 10 mm Hg in at least two anal manometry ports of 5 seconds' duration.

4 July 1995 RCTAL HYPRALGSIA IN IBS 43 xperimental protocol. The subjects were placed in a lateral decubitus position on a padded table. The examiner was always present but did not interact with the subjects after initial explanation of the respective task. The sequence of the different distention protocols was randomized. It was emphasized to the subjects that they had full control over the protocol by being able to deflate the balloon instantaneously at any time of significant discomfort or pain. Subjects had no visual or auditory cues to anticipate the type or time course of distentions. All experiments were performed following after a 12- hour fast and following the application of two Fleet enemas (C. B. Fleet Co., Inc., Lynchburg, VA). Quantification of Sensory Parameters Thresholds. Subjective thresholds for perception and the intensity of each type of distention-induced sensation were determined for the sensation of stool (innocuous sensation) and the onset of discomfort (aversive sensation). Thresholds during distention were expressed in reference to intrarectal pressure, rectal volume, and wall tension (for estimation of wall tension, see below). The influence of rectal compliance on sensory thresholds was controlled by measuring thresholds in terms of pressure or wall tension. Because the precise geometry of the rectum during balloon distention is not known, we estimated rectal wall tension by assuming either a sphere or a cylinder. For calculation of tension in a cylinder, we assumed a cylinder length of 11 cm (see balloon length, above). Radius at threshold was derived from the volume of the cylinder (V = ~r2l, in which L = 11 cm). (For the calculation of tension in a sphere, the radius was derived from the volume V = 4/3/~r 3.) In each case, wall tension (T) was calculated from the estimated balloon radius and the delivered pressure (p) at each stool and discomfort threshold using LaPlace's law (cylinder, T = 2pr; sphere, T = pr). Because the percentage of patients identified as low threshold and normal threshold were the same if tension was calculated based on a cylinder or a sphere, values assuming a cylinder are used throughout the report. Because we did not evaluate pain threshold or pain tolerance in the current study, the term hypersensitivity or low threshold is used to describe lowered thresholds for discomfort. The patient was given control over the distention pressure to prevent further distention once significant discomfort was experienced. This study design allowed us to minimize the potential emotional response associated with pain thresholds and pain tolerance and increased the subjects' acceptance of the test. Intensity. Intensity of sensation was determined during the phasic distention protocol by having the patient rate the intensity at each pressure step on a VAS ranging from no sensation (0) to severe (9). In contrast to the aversive descriptor discomfort used for threshold determinations, this scale measures primarily the intensity of sensations. 2 The intensity at the perception threshold was recorded for each subject at the lowest pressure step at which the given sensation was perceived (i.e., stool or discomfort). Viscerosomatic referral. During each phasic disten- A B R L L R 45% "l L Figure 2. Normal and abnormal referral of rectal distending stimuli. (A) Normal individuals experienced rectal distending stimuli only in the sacral dermatomal area indicated. (B) Patients with IBS referred sensations during rectal distention to sacral and to thoracolumbar dermatomes. The prevalence of major areas of referral are indicated. tion step, subjects were asked to mark the location of their respective sensation on a body map (Figure 2). 15 Validation Studies Response characteristics of the volume displacement device in vitro have previously been reported. 21 Validation of distention paradigm in vivo. It has been shown that thresholds determined in normal control subjects 15 are highly reproducible during a period of several months. To determine the reproducibility of sensory threshold determinations in patients with IBS performed on the same day, 7 patients underwent evaluation of thresholds in response to phasic and ramp distention twice, the two studies being separated by a 15-minute interval without balloon distention. There was no significant difference between the first and second studies in thresholds for stool and discomfort during either ramp or phasic distention. The correlation coefficient for thresholds determined twice was r = 0.91 for phasic distention and r = 0.87 for ramp distention. Statistical Analysis For comparison of means, an unpaired Student's t test was used. Relationships between pairs of variables were evalu-

5 44 MRTZ T AL. GASTRONTROLOGY Vo1.109, No. 1 ated using a Pearson r correlation coefficient. Z 2 analysis was used to compare proportional differences between groups. Significance was defined as P < 0.05 for all tests. mpirical subgroups of patients with IBS were formed based only on physiological parameters (not symptoms) using a K- means cluster analysis approach. 22 This statistical technique allows for empirical grouping of subjects based on data across multiple measures. ight measures from the anal manometry and rectal sensory testing of each patient were used to form the subgroups: resting anal pressure, squeeze anal pressure, stimulated anal pressure, rectoanal inhibitory reflex threshold, rectal discomfort threshold during ramp distention, rectal discomfort threshold during phasic distention, and rectal compliance (static compliance at 200 ml and compliance curve inflection point). Because the variables differed in scaling characteristics, each variable was standardized for the analysis. Cluster solutions with two-five subgroups were examined for statistical power using a pseudo F statistic, e3 The three-cluster solution had the highest F value and therefore represented the best fit to the data. The validity of the three-subgroup solution was further explored by comparing subgroup membership across a variety of physiological, psychological, and symptom measures (the same questionnaire and manometric measures were analyzed as in Results). Results The results are reported in five sections: (1) differences between patients with IBS and controls in the perception of rapid phasic and slow ramp distention of the rectum; (2) correlations between perception thresholds and self-reported symptoms and psychometric findings for the patients with IBS; (3) derivation of empirically defined subtypes of patients with IBS based on biological variables; (4) comparison of anal parameters to rectal sensitivity; and (5) comparison of longitudinal changes in perception thresholds with changes in self-reported symptoms during a 3-month period. Our major conclusions were that altered perception of rapid-phasic rectal distension--in the form of lowered thresholds for aversive sensations, increased intensity ratings, and viscerosomatic referral pattern--is present in almost all patients with IBS and that this abnormality represents a biological marker of IBS. Clinical Characteristics The clinical characteristics of the 100 patients with IBS are summarized in Table 1. Diarrhea was predominant in 14%, constipation was predominant in 53%, and 34% had alternating bowel habits. An average of 3.8 Manning criteria were reported. The most commonly reported symptom was a sensation of incomplete evacuation (87%). Seventy-three percent of patients reported a flare-up of symptoms within 24 hours of the rectal distention study, and 86% reported a flare-up within the 2 weeks before the study. Perception Thresholds and Viscerosomatic Referral Phasic distention. As shown in Figure 3A-C, mean thresholds for discomfort during rapid phasic distention were significantly lower in patients with IBS than in normal controls whether thresholds were expressed as intrarectal pressure, volume, or wall tension. Figure 3G shows the numbers of patients reporting discomfort at each pressure step. The median threshold for discomfort was 30 mm Hg lower in low-threshold patients than in the normal-threshold group. The intensity of perceived sensations at the discomfort threshold was significantly higher in the patients with IBS with normal thresholds than in the low-threshold patients with IBS and normal volunteers. (Figure 4A) However, overall, the patients with IBS had a similar intensity of symptoms at threshold as the normal controls. When intensity of the discomfort sensation was compared at each pressure (rather than at threshold), the patients with IBS as a group reported significantly higher intensities at pressures of --<40 mm Hg (Figure 4B). In contrast to the thresholds for discomfort, thresholds for stool (during phasic distention) were similar in patients with IBS and controls, as was the intensity of sensation at the threshold for stool. Intensity of the stool sensation at each pressure was also similar between patients with IBS and controls. Ramp distention. During slow ramp distention, mean perception thresholds for stool and discomfort were similar between patients with IBS and normals, regardless of whether thresholds were expressed as intrarectal pressure, volume, or wall tension (Figure 3D-F). Figure 5 shows a correlation of perception thresholds (expressed as wall tension) obtained during slow ramp distention and rapid phasic distention in all patients with IBS and in normal control subjects. Sixty-one percent of patients were hypersensitive for discomfort during phasic distention as measured by rectal pressure or wall tension (vs. none of the controls), but only 11% of patients were hypersensitive to discomfort during ramp distention. Similar percentages were obtained when thresholds were expressed as intrarectal pressure. No significant differences-in symptoms or symptom severity could be detected between the group that was hypersensitive to ramp distention and the group without ramp hypersensitivity. Age and sensation. Age significantly correlated with sensitivity during ramp distention, in which the tension threshold for discomfort increased by 0.8 mm

6 July 1995 RCTAL HYPRALGSIA IN IBS 45 4 I 30 3oo B 125 C 100 g.= i 75 5O i 25 6O D 400! 0, r 125 r o = i/ == // i 100 x 75 - so 25 o - 3O ~ 18 G >50 Pressure Step (ram Hg) Figure 3. Discomfort thresholds during rectal distention. (A-C) During phasic distention, patients with IBS ([]) have lower thresholds than normal controls (C]) whether (A) pressure, (B) volume, or (C) tension is measured. Values are shown as mean +_ SM; P < (D-F) During slow ramp distention, patients with IBS and controls have similar thresholds. Values are shown as mean ± SM. (G) Number of patients with low (I) and normal ([]) thresholds for discomfort at each pressure step during phasic distention. Normal threshold cutoff was based on 95% confidence interval for wall tension thresholds as shown in Figure 5. There was overlap (1 patient) in threshold pressures between the two groups; the median values for the two groups were separated by six pressure steps. Low threshold (n = 61): mean, 18 mm Hg; median, 20 mm Hg. Normal threshold (n = 39): mean, 47 mm Hg; median, 50 mm Hg. Hg X cm for each additional year of age (P < 0.025). The IBS group hypersensitive to phasic distention was younger with a mean age of 42 years compared with 49 years for the normosensitive group (P < 0.05), although by linear regression the correlation between age and phasic threshold was not as strong as that for ramp distention (P < 0.4). Symptoms and viscerosomatic referral during rectal distention. Rectal balloon distention reproduced characteristic symptoms (lower abdominal pain, rectal fullness, urgency) in 69% of patients with IBS. In 83% of subjects, the referral area during rectal distention over- lapped with the area of primary discomfort indicated on the questionnaire at initial presentation. Reproduction of symptoms was more common in the low-threshold group (75%) than in the normal-threshold patients (53%). Seventy-nine percent of patients with IBS referred sensations during rectal distention to the lower abdomen or suprapubic area (dermatomes T10-L3) compared with 7% of normal subjects (P < 0.001) (Figure 2). Ninetythree percent of normal subjects referred all sensations to the perianal area ($3 dermatome) up to pressures of 50 mm Hg. The patients with IBS also referred sensations

7 46 MRTZ T AL. GASTRONTROLOGY Vol. 109, No. 1 to the $3 dermatome in addition to the abdominal referral. Low-threshold patients were nearly twice as likely to have abdominal (not including suprapubic) referral patterns (56%) than normal-threshold patients (3098). Sex and age did not significantly affect referral patterns. Altered rectal perception, manifest by either a low threshold or increased intensity for aversive sensations or by aberrant referral, was found in 9498 of the patients but in only one normal control (7%). In summary, in IBS there is rectal hypersensitivity to rapid distention that is limited to the perception of o O g~ ag W e- = 7 ~ ~ i i 6 t 3 L 2 4 g~ ~, ~ 3 i- _= L Low Threshold IBS Normo- IBS I I I I I I Pressure (mm Hg) I Normal Controls Figure 4. Intensity of discomfort sensation. (A) During phasic rectal distention, normal-threshold patients with IBS ([]) perceived threshold stimuli more intensely than low-threshold patients with IBS (3) or controls ([]). Values are shown as mean +_ SM; *P < (B) Patients with IBS as a whole perceived phasic rectal distention more intensely than controls at pressures up to 40 mm Hg. Values are shown as mean +_ SM; *P < intensity of perception in A and B was estimated by VAS as described in Materials and Methods. V, IBS; O, control. L discomfort, an aversive sensation. In patients with IBS, rectal balloon distention typically induces abnormal referral to areas outside of the sacral dermatomes. This distention commonly reproduces the patients' symptoms. Differences in Somatic and Psychological Symptoms Between Low-Threshold and Normal-Threshold IBS Groups Patients' assessment of bowel habits (normal, diarrhea, constipation, or alternating by questionnaire) indicated a significantly greater percentage of patients with diarrhea in the low-threshold group (P < 0.05) (Table 1). Symptoms of rectal fullness were reported by 44% of the low-threshold group but only 28% of the normalthreshold group (P < 0.05). Of the patients who reported some episodes of diarrhea (n = 38), the frequent passage of normal stools was found in 26% of the low-threshold group but in none of the normal-threshold group (P < 0.05). Patients were given a list of nine complaints referable to the gastrointestinal tract (retrosternal pain, retrosternal pressure, abdominal fullness, abdominal gas, abdominal bloating, bloating with distention of the belly, rectal fullness after a bowel movement, nausea, and belly pain) and asked to select one or more that caused the most 250 I I I z " i o 150 g o C w 100 o P C I I I i Phasic Tension Threshold (mm Hg x cm) Figure 5. Rectal discomfort thresholds during different types of distention, Patients with IBS have lower thresholds for discomfort during phasic rectal distention but not ramp distention. Shown are thresholds (expressed as wall tension) for phasic and ramp distention for patients with IBS (0) and normal controls (V), The shaded area is the average tension threshold for normals _+ 2SD.

8 July 1995 RCTAL HYPRALGSIA IN IBS 47 Table 2. Psychological Symptoms and Rectal Sensitivity in IBS Low- Normalthreshold threshold IBS (%) IBS (%) All IBS (%) Psychological symptom (n = 61) (n = 61) (n = 100) Somatization Obsessive/compulsive Interpersonal sensitivity Depression Anxiety Hostility Phobic 31 a Paranoid Psychosis Any ap < 0.05 for comparison of low-threshold IBS and normal-threshold IBS. distress at the time of the initial clinic visit. The lowthreshold group selected 30% more of these complaints than the normal-threshold group (P < 0.02). Symptoms generally not thought to originate solely from the rectum (but possibly resulting from other bowel areas), such as abdominal bloating and distention, cramping with bowel movements, and relief of abdominal pain after movements, did not correlate well with rectal perception thresholds (Table 1). Symptom severity and quality of life. The mean VAS score for overall symptom severity was not significantly different between normal-threshold (4.5 of 9) and low-threshold (4.8 of 9) patients with IBS. Similarly, there was no difference in the number of patients who reported an acute flare-up within 24 hours (73%) or within 2 weeks (86%) of the rectal sensory testing between the two groups. There also was no difference between groups in terms of the four quality-of-life measures. Correlation of perception thresholds with psychological symptoms. A significant level of psychological symptomatology, as indicated by at least one SCL-90 score of 63 or above, was present in 73% of patients with IBS (Table 2). The most common symptoms were somatization (45%), depression (42%), interpersonal sensitivity (39%), and obsessive-compulsive ideation (38%). Although severity of phobic trait correlated inversely with sensory thresholds (more phobic, lower threshold, r = 0.29, P < 0.05), no other SCL-90 scale had such a correlation. Anal Manometry and Rectal Sensitivity There was no relationship between anal canal pressures (resting, squeeze, stimulated) or paradoxical anal sphincter contraction and rectal sensitivity in IBS. There was also no relationship between thresholds for the rectoanal inhibitory reflex and perception thresholds. Cluster Analysis As described in Materials and Methods, patients with IBS were separated into three subgroups based on a K-means cluster analysis of the eight physiological parameters. The means and Ss of the eight variables used to form the subgroups are shown in Table 3, along with three other objective and 10 subjective parameters. As shown in Table 3, group I comprised patients with hypersensitivity to phasic rectal distention and elevated anal pressures at rest and with stimulation. Analysis of other variables showed this group to be younger and symptomatically almost four times as likely to have diarrhea and less likely to have constipation. Group II comprised patients with normal sensitivity to phasic rectal distention and marked hyposensitivity Table 3. Objective and Subjective Measures in Three IBS Subgroups by Cluster Analysis Objective variable No. of subjects 30 % Female 59 Age (yr) 34 _+ 2 ~ Anal pressure a Rest 109 _+ 4 ~ Stimulated Squeeze ~ Rectoanal inhibitory threshold a (ram Hg) 14.0 _+ 1 Discomfort threshold (tension) a Ramp ~ Phasic 27.2 ± 4 c Complicance a Static at 200 ml (ml/mm Hg) 7.4 _+ 1 Inflection point (ml) 75.8 _+ 15 Subjective parameters Constipation (%) 40 b Diarrhea (%) 27 b Alternating constipation and diarrhea (%) 33 Hard stools (%) 52 Stools/wk (%) _ 1 <3 stools/wk (%) 26 Gas/bloat (%) 77 Incomplete evacuation (%) 97 Symptoms severe (%) 20 Altered referral of sensations (%) 72 Primary symptoms (n) 3.2 _+ 0.3 NOT. Values are shown as means _+ SM. avariables used for cluster subgroupings. ~P < 0.05, cp < 0.01, Op < 0.001; I vs. II. ~P < 0.05, ~P < 0.01, gp < 0.001; II vs. Ill. hp < 0.05, ~P < 0.01, JP < 0.001; Ill vs. I. Group I Group II Group III ± 3 48 ± 3 j j 112 ± _+ 5 j 175_ ±8 j 14.4 ± _ ± 10 ~ 83.5 ± e 14.8 ± 2 h 5.9_+ 1 ~ 11.3_+ I h 55.1 ± 14 ~ h i 7.1 _ I h h 52 e e 69 h h _ h

9 48 MRTZ T AL. GASTRONTROLOGY Vo1.109, No ~ I I Phasic Discomfort Change (mm Hg) Change in I I I IBS symptoms Figure 6. Changes in IBS symptoms compared with changes in rectal sensitivity. Improvement or worsening in IBS symptoms (abdominal pain or bloating) during a 3-month period is paralleled by an increase or decrease in rectal discomfort thresholds to phasic distention. (P < 0.05 compared with controls) to ramp distention. The group was more likely to have constipation and least likely to report gas as a primary problem. Subjects in group III were most hypersensitive to phasic rectal distention and had increased rectal compliance (compared with the other groups and with controls; P < 0.05). They were likely to have constipation, hard stools, and fewer than three stools per week. They reported more symptoms as primary (4.4/9 vs. 3.2/9 in the other groups) and were more likely to report their symptoms as severe. Temporal Variations in Perception Thresholds and Symptoms Variations in symptom severity and perception thresholds during a 3-month period were assessed in 15 patients with IBS. Based on their initial perception threshold for phasic distention, 11 (73%) had low thresholds and 4 (27%) had normal thresholds. As shown in Figure 6, there was a significant correlation (P < 0,01) between retrospective reports of change in the severity of abdominal pain or discomfort and change in threshold for discomfort with phasic distention. Four of 11 lowthreshold subjects (36%) developed normal thresholds in the 3-month period, and this change was associated with an improvement in symptoms. Of four initially normalthreshold subjects, one became low threshold. No patients had an improvement in symptoms accompanied by a lowering of thresholds; likewise, no patients had a worsening of symptoms accompanied by an increase in thresholds (P < 0.01). Three patients had no change in symptoms but showed significant changes in thresholds. There was no correlation between a temporal change in symptoms and changes in stool thresholds during phasic distention or in stool or discomfort thresholds during ramp distention. Discussion We report the first large study of patients with IBS that used clearly defined modes of rectal stimulation, a standardized bowel symptom questionnaire, and longitudinal evaluation of symptoms and rectal perception thresholds. We found that 94% of the patients studied had evidence for altered perception of aversive rectal sensations manifested as lowered thresholds, an increased intensity, or an altered viscerosomatic referral pattern. The simultaneous recording of pressure and volume of the rectum during distention allowed us to estimate thresholds for perception in terms of pressure and wall tension. Therefore, the observed differences in thresholds cannot be accounted for by interindividual differences in rectal compliance. We have previously provided evidence to suggest that perception of slow rectal distention is mediated by tension receptors of sacral afferents, whereas rapid phasic distention may stimulate preferentially splanchnic afferents with receptive fields in serosa and mesentery and projecting to the lumbar spinal cord. 24 Therefore, we used two different distention paradigms in an attempt to stimulate these different afferent nerve pathways. In contrast to a previous study that reported a similar prevalence of low rectal perception thresholds (60%) in patients with IBS, 6 the current study design allowed us to determine that the rectal hypersensitivity (in the form of lowered thresholds or increased intensity) was stimulus specific and was restricted to sensations perceived as aversive. Thus, lowered perception thresholds were found only during rapid phasic stimulation in the isobaric mode, whereas stool and discomfort thresholds during slow ramp inflation of the rectum were normal or even increased in some patients. We assume that in earlier studies, handheld syringes administered rapid inflations similar to the phasic stimulation used in the current study (N. Read, personal communication, 1993). Similar to the findings of Whitehead et al., 25 we found that lowered perception thresholds in IBS were restricted to aversive sensations (discomfort), whereas stool thresholds did not differ from normal control subjects. In addition, the patients with IBS who had normal phasic thresholds for discomfort reported increased intensity of sensations compared with normal controls. For the whole IBS co-

10 July 1995 RCTAL HYPRALGSIA IN IBS 49 hort, intensity of aversive sensation (but not stool sensation) was significantly higher at pressures at 40 mm Hg and lower. The combination of aberrant referral of rectal stimuli to thoracolumbar dermatomes reported here and in previous studies, 26'2r together with the lowered thresholds limited to rapid phasic distention and to visceral sensations perceived as noxious, suggest the involvement of splanchnic afferents with receptive fields in the serosa and mesentery, projecting to the thoracolumbar cord. 24 In contrast, normal or even elevated thresholds during slow ramp distension are likely to be mediated by tension receptors in the rectal wall projecting to the sacral spinal cord. 21 In the normal individual, splanchnic pathways are not required for the experience of normal rectal sensations, 28 whereas electrical stimulation of these pathways is experienced as pain. 29 A selective increase in the excitability of these neurons may explain the altered perception in IBS, which can occur in the presence of normal perception of sensations mediated by other types of rectal afferents. There are several possible explanations for the observed patterns of altered rectal perception. Because normalthreshold patients reported increased intensities of discomfort at threshold, one could argue that these patients did not indicate their true threshold and subsequently reported a higher intensity at the following pressure step. Two observations argue against such a hypothesis. First, the median pressure step perceived by the normal threshold group as discomfort was 50 mm Hg (mean, 47 mm Hg) whereas it was 20 mm Hg (mean, 19 mm Hg) in the low-threshold group. Because there are six 5-mm Hg pressure steps between the medians, it is unlikely that normal-threshold patients simply missed their true discomfort threshold and then reported a higher-threshold pressure as more intense. Second, patients with IBS as a whole rated increased intensities of perception at each pressure step > 2 5 mm Hg. An alternative explanation for the observed patterns of rectal perception may be related to the fact that patients with IBS (mis)label rectal sensations as discomfort at lower degrees of rectal distention than normal controls. It has recently been suggested that this type of response bias may be responsible for lower perception thresholds in patients with noncardiac chest pain 3 and with IBS. 31 Although this hypothesis was not tested specifically in this study, several observations make such an explanation unlikely. First, thresholds to slow rectal distention were normal in the majority of subjects and even elevated in a subgroup. Second, the affective sensation experience is heightened by anxiety, 32 and anxiety as a trait was not more common in hypersensitive patients. Third, intensity of sensation is not an affective parameter 32 and was clearly elevated in the patients with IBS. Finally, altered viscerosomatic referral, a parameter generally not experienced in affective terms, was present in the majority of the patients with IBS. Price and Harkins 32 suggested that affective and pure sensory components of pain may be mediated by different central pathways and that the differential involvement of these components can be assessed using rating scales with affective and sensory descriptors. 33 Although affective descriptors and intensity of perceived sensations were not assessed systematically in this study, it is conceivable that whereas all patients with IBS show alterations in rectal perception, in some patients this abnormality is expressed more in terms of affective descriptors (discomfort) and in others is expressed in terms of intensity measures. Consistent with previous reports on patients with IBS seen at tertiary referral centers, 6 greater than normal levels of psychological symptoms (assessed by a simple psychometric instrument) were found in the majority of our patients. In accord with findings by Whitehead et al., 5 psychological symptoms did not correlate well with rectal perceptual thresholds, suggesting that the severity of psychological symptoms is not causally related to rectal hypersensitivity. In contrast to psychological symptom severity, we have found that certain IBS symptoms presumably mediated by rectal afferent pathways correlate with rectal perception thresholds. For example, the sense of persistent rectal fullness, and in patients with diarrhea frequent evacuations of the rectum, was more common in the low-threshold group. In contrast, symptoms that may be mediated preferentially by intestinal afferents, such as abdominal bloating and distention, cramping with bowel movements, and relief after defecation, did not correlate well with rectal perceptual thresholds. In view of previous reports suggesting lowered perception thresholds in the small intestine, 4 it is therefore conceivable that symptoms such as abdominal cramping or bloating reflect colonic and/or intestinal in addition to rectal hypersensitivity. Rectal perception thresholds did not correlate with other reflex activities of the internal or external anal sphincter. These findings indicate that afferent pathways involved in rectal hypersensitivity differ from intrinsic and extrinsic reflex pathways modulating the anal sphincter muscles Traditionally, attempts to classify patients with IBS into distinct subgroups have been largely based on subjective symptoms such as predominant bowel habits or

11 50 MRTZ T AL. GASTRONTROLOGY Vol. 109, No. 1 predominant symptoms (e.g., pain vs. bloating). However, it has recently been questioned if bowel habits identify a physiological subset of patients with IBS. 34 Furthermore, clinical observations suggest that the predominant bowel pattern can change during a patient's lifetime. To differentiate patients based on the full pattern of their physiological measures instead of symptoms or a single parameter (such as phasic discomfort threshold), we used a cluster analysis procedure. We identified three possible IBS subgroups based on distinct patterns of such biological variables as anal canal pressure, perception thresholds, and rectal compliance. The three identified subgroups were replicated across a random split of our sample, indicating reliability of the classification. Although there was much overlap in symptoms, the groups did show differences in symptom patterns that may be associated with differences in physiological parameters. One group is younger and has rectal hypersensitivity and a hypertensive and hyperresponsive anal sphincter. The group is notable symptomatically for a higher prevalence of diarrhea and on average twice the frequency of bowel movements as the other groups. A second group has normal sensitivity to rapid phasic distention and hyposensitivity to slow ramp distention, is least phobic psychologically, and is predominantly constipated. The third group has the greatest degree of rectal hypersensitivity and shows elevated rectal compliance; symptomatically, they report the greatest number of primary symptoms, are most likely to report their condition as severe, and are predominantly constipated. The identification of subgroups of patients with IBS based on differences in biological parameters may have important consequences for the evaluation of potential therapies and is likely to stimulate further investigations into the etiology of this syndrome. For example, the data presented here suggest that among patients with lowered discomfort thresholds there are two subgroups, one with increased rectal compliance and higher incidence of constipation and hard stools (group III) and one with a higher incidence of diarrhea (group I). In addition, as shown in Table 3, patients reporting constipation may come from any of the subgroups and therefore have widely different patterns of anorectal physiology. The failure to distinguish effective therapies in many published trials may be explained partially by the heterogeneity of biological parameters in patient subgroups based on predominant bowel habits. Further replication of the three subgroups in other populations of patients with IBS is needed as well as further study of the symptomatic correlates of these patterns of physiological parameters. If replicated, our data suggest several hypotheses regard- ing the differences in pathophysiologies between the three groups, assuming some altered rectal perception (expressed as lowered threshold, increased intensity, or altered viscerosomatic referral) is shared by all patients. Plausible mechanisms explaining the differences between clusters are differential activation of descending bulbospinal pathways and of autonomic effector responses. 35 Neurons in the locus ceruleus are in a unique position to mediate such differential effector responses in response to visceral stimuli: (1) they can be activated by environmental stresses and by colonic distention, responding more to rapid phasic than to gradual distention36; (2) they regulate both sympathetic and sacral parasympathetic outflow; and (3) they play an important role in noradrenergic bulbospinal pain modulation systems. 37 For example, the combination of increased perception thresholds observed during slow ramp distention with normal perception thresholds to phasic distention (group II) may represent effective activation of endogenous pain modulation mechanisms in response to visceral irritation with resulting reductions in sensitivity to aversive slow distention (encoded by tension receptors of sacral afferents in the rectal wall). 3. The marked rectal hypersensitivity associated with increased rectal compliance in the older patient group with predominant constipation (group III) may represent the contribution of the agerelated increase in sympathetic tone previously described. 39 Colonic motor neurons are under tonic sympathetic inhibition, and a regional increase in the activity of sympathetic efferent pathways 4 may produce a decrease in tonic motor activity resulting in increased rectal compliance. 24 Similarly, intestinal water handling by epithelial cells is under extrinsic sympathetic control with increased sympathetic tone resulting in decreased secretion. 41 The dry, small-volume stools reported in group III may therefore reflect increased net intestinal absorption of water, mediated by increased activity of sympathetic secretomotor neurons, just as the increased prevalence of loose and liquid stools observed in group I may reflect a reduced sympathetic epithelial modulation. Because changes in function-specific sympathetic neurons (such as lumbar secretomotor or motility regulating sympathetic nerves modulating the intestine and the rectum) can occur in the absence of systemic sympathetic changes, ~v future studies should address regional autonomic abnormalities that may be manifest by altered intestinal compliance, fluid and electrolyte handling, and mucus secretion. Superimposed variations in overall autonomic activity related to environmental stressors, psychopathology, and age may contribute further to the wide spectrum of observed symptoms.

12 July 1995 RCTAL HYPRALGSIA IN IBS 51 It has previously been suggested that symptomatic improvement in response to short- and long-term therapeutic interventions in patients with IBS is associated with a normalization of rectal hypersensitivity. 42 Longitudinal studies reported here indicate that for a given individual with IBS, perceptual thresholds for discomfort in response to phasic stimulation do correlate with retrospective reports of changes in the severity of abdominal pain and/or discomfort. Although patient numbers were small, the reported symptom changes may have been affected by memory bias, *3 and a small number of patients (3 of 15) showed changes in thresholds without associated symptom changes, our findings suggest that rectal perception thresholds are a potential surrogate marker for IBS symptom severity: (1) abdominal ratings in patients with IBS have been shown to correlate well with symptom severityl2; (2) constant thresholds for stool during phasic distention and thresholds during slow ramp distention in the same time period further emphasize the specificity of the involved pathways and make it unlikely that the observed changes in discomfort thresholds were attributable solely to memory bias, chance, or habituation; and (3) the observed correlations were independent of any specific therapeutic intervention, suggesting a general phenomenon. Although longterm longitudinal studies are needed, our observations support the notion that rectal hypersensitivity is involved in symptom generation rather than being a constant trait, the expression of which is modified by other stimuli (such as altered motility). Thus, measurements of longitudinal changes in rectal sensitivity may be useful as a biological parameter in monitoring the efficacy of medications directed at certain IBS symptoms. References 1. Drossman DA, Thompson GW, Talley N J, Funch-Jensen P, Janssens J, Whitehead W. Identification of subgroups of functional gastrointestinal disorders. Gastroenterol Int 1990;3: Snape W J, Carlson GM, Cohen S. Colonic myoelectric activity in the irritable bowel syndrome. Gastroenterology 1976;70: Snape W J, Wright SH, Battle WM, Cohen S. The gastrocolonic response: evidence for a neural mechanism. Gastroenterology 1979; 77: Kellow J, Miller U, Phillips SF. 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