Enteric coating of a capsule has been used to deliver a bolus of radioisotope to the ileocecal region. This has allowed quantitative assessment of regional ...
Digestive Diseases and Sciences. Vol. 3S. No. 6 Uune 1993k pp. 996-1003
Quantitative, Noninvasive Assessment of Antidiarrheal Actions of Codeine Using an Experimental Model of Diarrhea in Man L. BARROW, K. P. STEED, R. C. SPILLER, N. A. MASKELL, J. K. BROWN, P. J. WATTS, C. D. MELIA, M. C. DAVIES, and C. G. WILSON
Enteric coating of a capsule has been used to deliver a bolus of radioisotope to the ileocecal region. This has allowed quantitative assessment of regional colonic transit in a group of healthy subjects whose proximal colonic transit was accelerated by lactulose 20 ml thrice daily. In this experimental model of diarrhea, codeine delayed transit from mouth to terminal ileum and also delayed transit through the ascending colon from 5.3 ± 2.5 hr to 7.4 ± 2.5 hr, N = 11, P < 0.05. Furthermore, codeine delayed whole colon transit, as assessed by geometric center analysis, which showed the delay to be most marked in the right colon with little effect noted in the left colon. In addition, codeine significantly reduced the number of retrograde movements observed and reduced the colonic response to eating. The antidiarrheal effect of codeine appears to be due to a combination of delayed mouth-cecum transit plus an additional delay in the ascending colon. Tfiis colonic delay may be partially explained by a reduction in postprandial propulsive movements that were seen in this model of diarrhea. KEY WORDS: colonic motility; transit: lactulose; codeine; opiates.
Codeine is a highly effective antidiarrheal agent, used to reduce stool volume and frequency in a wide range of chronic diarrheal states, such as short bowel syndrome, ileostomy, and post hemicolectomy diarrhea (1). Despite its known efficacy, few studies have been made of its site of action in man. Two recent studies indicate that codeine has a powerful effect on small bowel motility, delaying mouth-cecum transit in postvagotomy diarrhea (2) and causing pooling of fluid in the upper small Manuscript received March 23, 1992; revised manuscript received September 15, 1992; accepted December 17, 1992. From the Departments of Physiology and Pharmacology, and Therapeutics, Queen's Medical Centre, Nottingham; and Pharmaceutical Sciences, University of Nottingham, UK. This research was funded by a collaborative award from SERC and Reckitt & Colman Products Ltd. Address for reprint requests: Dr. R. C. Spiller, Department of Therapeutics, University Hospital, Queen's Medical Centre, Nottingham. NG7 2UH, UK.
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intestine in normal volunteers subjected to rapid intragastric infusions of saline (3). This latter study suggested that codeine had little impact on colonic transit, although this was likely to be due to the colonic absorptive capacity being overwhelmed by the high flow rates used, these being more characteristic of acute infectious diarrheas than the chronic diarrheal states described above. We have recently developed an experimental model of moderate diarrhea using lactulose syrup, 20 ml thrice daily in healthy subjects, to accelerate proximal colonic transit (4), which is assessed by gamma scintigraphy. The method is accurate, noninvasive and, we believe, provides a good model for the diarrheas caused by an increased ileocolonic inflow, such as in lactose intolerance, malabsorption, and short bowel syndromes. The report that follows uses this technique to show that codeine, in
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ANTIDIARRHEAL ACTIONS OF CODEINE normal clinically effective doses, delays both small bowel and proximal colonic transit in subjects with moderate diarrhea. Since previous reports (5) have suggested the possibility that diarrhea is characterized by differential transit of liquids and solids, we administered separately labeled finely ground resin (0.2 mm diameter) and 5-mm particles to assess differential transit of these extremes of particle size. MATERIALS AND METHODS Subjects. Twelve healthy subjects (six men, six women), median age 20 years (range 19-26 years), underwent paired colonic transit studies while taking lactulose with or without codeine ingestion. Volunteers were excluded from the study if they were known to suffer from gastrointestinal disease, had a stool frequency of 3/day, were taking medication likely to alter intestinal motility or were on a vegetarian or "non-Western" diet. Specific exclusions also covered excessive alcohol intake or excessive smoking. All females were required to test negative for urinary human chorionic gonadotropin on ihc morning prior to the imaging day. Written informed consent was obtained from all subjects, and the study was approved by the University of Nottingham Medical School Ethics Committee and carried out according to the guidelines in the Declaration of Helsinki (Venice amendment 1983). Capsule Preparation. Two sizes of particles (0.2 mm and 5 mm) were radiolabeled. The 5-mm particles were prepared from Amberlite IRA-410 resin mixed with ethylcellulose (0.1% w/w) to give a nondisintcgraling tablet of 5 mm diameter and 3 mm depth. Each tablet was radiolabeled with ['^''Tcjpertechnetatc to give 0.67 MBq/ tablet at the time of dosing and was coated with polymethylmethacrylate in acetone to prevent leaching of radioactivity. The 0.2-mm particles were Amberlite IR-120 ion-exchange resin beads (180- to 250-u.m size range) and were radiolabeled with indium-Ill chloride to give 0.33 MBq/100 mg of resin at the time of dosing. Hard gelatin capsules were each filled with three of the Wm Tc-labcled 5-mm-diameter ethylcellulose tablets and ISO mg of "'In-labeled 0.2-mm resin particles. Finally, the capsules were coated with an acid-resistant polymer to afford protection against disintegration until reaching the distal small bowel. Each study day exposed the subjects to 0.368 mSv, giving a total radiation dose of 0.736 mSv, of which most (0.6 mSv) was from the indium. Study Protocol. The study had a randomized crossover format, divided into two parts (A and B), each of four days duration and separated by a two-weck washout period. Subjects observed a standard 20-g fiber diet on days 1-3, which excluded pulses, cathartic foods, and excess alcohol. A set menu was consumed by all subjects on each of the two imaging days (day 4 of the protocol), which provided a light breakfast, a lunch-time 600-kcal meal and a 1000-kcal evening meal. In parts A and B, on days 1-4 inclusive, subjects ingested lactulose solution 20 ml thrice daily designed to approximately double stool frequency. In part B subjects also ingested codeine phosDigestive Diseases and Sciences, Vol 38, No. 6 (June 1993)
phate tablets 30 mg twice daily on days 1 and 2 and 30 mg four times daily on days 3 and 4. During parts A and B, days 1-4 inclusive, all subjects recorded bowel movements in a stool diary. Scintigraphic Imaging. All subjects attended on each of the two imaging days (day 4 of the protocol) having fasted from the previous evening. Anterior and posterior reference markers, comprising radiolabeled filter-paper (0.25 MBq ("Tclpertcchnetate) contained within a sheath of waterproof tape, were taped on to the abdomen over the right lobe of the liver at the level of the pylorus and were used to align successive scintigraphic images during analysis. Each subject then ingested two of the entericcoated, radiolabeled capsules with 150 ml of water. Anterior and posterior gamma scintigraphic images (30 sec duration) were recorded using an IGE Maxicamera II (IGE Ltd., Herts, UK) fitted with a medium energy parallel hole collimator (300 keV maximum energy). Separate views were acquired using 20% symmetrical energy windows centered on the 141-keV and 245-kcV photopeaks of Wm Tc and '"In, respectively. The images were stored in a 128 x 128 matrix using a dedicated Nuclear Diagnostics computer system (Gravcscnd, Kent, UK). Images were recorded immediately after dosing and at 30-min intervals throughout the day for 16 hr with a final anterior-posterior image pair at 24 hr after dosing. Subjects stood in front of the detector during imaging and were fed after the capsules were seen to leave the stomach. Scintigraphic Analysis. The disintegration point of the capsules was visually assessed from the scintigraphic images, the terminal ileum being identified as the place at which the capsules remained relatively static for often two or three sequential images before the isotope was seen to move anteriorly and to disperse in the ascending colon. Transit of the two particle sizes was subsequently monitored through the colon regions. All scintigraphic data were corrected for background radiation, radioactive decay, and tissue attenuation using the geometric mean of the anterior and posterior counts for each particle size (6). The corrected counts were expressed as percentage activity of the total radioactive dose delivered to the colon. After reviewing the whole series of scintigraphic images, an outline of the colon was constructed for each subject. For analysis of transit times, this outline was divided into three regions of interest and superimposed onto each scintigraphic image (Figure 1). The radioactivity in each region of interest was thereby determined and time-activity curves constructed to express the transit of particles through the regions. Mean transit times (MTT) of 0.2-mm and 5-mm particles through the ascending colon were calculated from the difference between the time when 50% of the activity lay in or beyond the ascending colon and the time when 50% of the activity had passed the hepatic flexure (Figure 2). Owing to increased scatter and a decrease in counting efficiency in the pelvis, we took the maximum number of corrected counts lying within the colon to be 100% of the dose rather than the initial activity first recorded in the stomach immediately after ingestion. The effect of eating on transit through the proximal colon was determined in those subjects in whom counts in
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Si
14-, 1210
3-
86-
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* *
41-
*#*
2Lactulose
Lactulose + codeine
Fig 5. Stool frequency, expressed as the mean number of bowel movements per day over a four-day period, in the lactulosetreated subjects and the lactulose-treated subjects taking codeine. Values significantly different from the corresponding values in the lactulose-treated subjects are denoted as ***p < 0.01.
the radiolabeled particles within the colon. Clear, substantial retrograde movements of the 5-mm particles were occasionally noted between sequential images and were defined as the backward movement of one or more particles through at least one colonic segment, divided as in Figure 4. Statistical Analysis. Results are expressed as means ± SD. Significant differences between paired data were determined by the Wiicoxon signed-rank sum test and between means of pooled data by the Mann-Whitney U test; these nonparametric tests were used since the data were not normally distributed. RESULTS Symptoms and Stool Frequency. Eleven subjects successfully completed the whole protocol and their stool diaries showed that the lactulose-induced diarrhea was successfully reversed by coadministration of codeine. Stool frequency was 2.4 ± 1.0 times/day in the lactulose-treated subjects, significantly greater than the 1.2 ± 0.4 times/day (P < 0.01) in the lactulose-treated subjects taking codeine (Figure 5). Capsule Disintegration. Visual assessment of scintigraphic images showed reliable delivery of capsules into the ileocecal region where disintegration occurred and no capsule was observed to reDigestive Diseases and Sciences, Vol. 38, No. 6 (June 1993)
Lactulose
Lactulose + codeine
Fig 6. Capsule arrival time (hours after dosing) in the terminal ileum in lactulose-treated subjects and in lactulose-treated subjects taking codeine. Values significantly different from the corresponding values in the lactulose-treated subjects arc denoted as "P < 0.02.
main intact beyond the mid-ascending colon. Arrival of the capsules in the terminal ileum occurred at 2.8 ± 1.0 hr (N = 11) after dosing in the lactulosetreated subjects. Effect of Codeine. Coadministration of codeine to lactulose-treated subjects significantly lengthened mouth to terminal ileum transit time of the capsules, which rose from 2.8 ± 1.0 hr (/V = 11) to 5.3 ± 3.2 hr (TV = 11, P < 0.02) (Figure 6). This was associated with a delay in radioisotope entry into the colon (Table 1) and a further delay in the transit through the ascending colon, which rose from 5.3 ± 2.5 hr to 7.4 ± 2.5 hr (N = 11, P < 0.05) (Figure 7). Similarly, codeine significantly delayed transit of the 5-mm particles through the ascending colon, the mean transit time rising from 4.7 ± 3.4 hr to 10.4 ± 7.7 hr (N = 11, P < 0.02). This delay in transit was also reflected in the percentage of 0.2-mm particles remaining in the ascending colon at 24 hr after dosing, which rose from 12.4 ± 8.2% (N = 11) in the lactulose-treated subjects to 23.9 ± 7.3% with codeine (P < 0.05, N= 11). The effect of codeine in delaying transit was also seen from geometric center calculations for the 5-mm particles, the most obvious effect being seen
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BARROW ET AL TABLE 1. ARRIVAL TIME (HOURS ArrER DOSE) OF 50% OF 0.2- AND 5-MM PARTICLES IN ASCENDING COLON AND POST-ASCENDING COLON REGIONS AND MEAN TRANSIT TIME OF 50% OF PARTICLES WITHIN ASCENDING COLON IN LACTULOSE-TREATED SUBJECTS AND LACTULOSE-TRUATED SUBJECTS TAKING CODEINE*
Treatment group (N = //)
Arrival time (hr) of 50% of activity in whole colon
Arrival time (hr) of 50% of activity beyond hepatic flexure
Mean transit time (hr) of 50% of activity in ascending colon
3.8 ± 1.6 6.3 ± 2.8a
9.5 ± 2.9 13.4 ± 2.0c
5.3 ± 2.5 7.4 ± 2.5a
3.8 ± 1.7 6.3 ± 2.9a
8.9 ± 3.5 16.1 ± 7.3c
4.7 ± 3.4 10.4 ± 7.7b
0.2-mm particles Lactulose Lactulose + codeine 5-mm particles Lactulose Lactulose + codeine
'Values significantly different from the corresponding values in the lactulose-treated subjects are denoted as a, P < 0.05, b, P < 0.02, andc, P< 0.01.
in the right colon. At 6 hr after dosing, the mean geometric center was 1.8 ± 1.1 during codeine treatment, significantly less than the value of 3.0 ± l.2(N=U,P< 0.02) in lactulose-treated subjects. Similarly, at 12 hr after dosing, the mean geometric centers were 3.3 ± 1.6 and 5.2 ± 1.7 (N = U, P < 0.02) respectively. However, at 24 hr after dosing when the activity had reached the left colon, the differences were less marked although still significant, the geometric centers being 5.1 ± 1.4 during codeine treatment compared with values of 6.2 ± 1.5 (N = 11, P < 0.05) with lactulose treatment. Effect of a Meal. Although the study was not designed to assess the effect of eating, we did note 14n
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4-
DISCUSSION
20 Lactulose
Lactulose + codeine
Fig 7. Mean transit time (hr) of 0.2-mm particles through the ascending colon (MTT-AC) in lactulose-treated subjects and in lactulose-treated subjects taking codeine. Values significantly different from the corresponding values in the lactulose-treated subjects are denoted as *P < 0.05.
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an apparent difference in the meal effect in those subjects in whom radioactivity in the ascending colon had reached a plateau {N - 9 with lactulose treatment and N = 11 during codeine cotreatment). The mean slope of the time-activity curves for the ascending colon, calculated over the 2 hr before and the 2 hr after the meal, fell after the meal by 7.6 ± 2.3% hr (N = 9) in lactulose-treated subjects. Codeine significantly reduced this fall to 5.3 ± 3.2% hr (N = 11, P < 0.05). Retrograde Movements. Nine of 11 lactulosetreated subjects and seven of 11 lactulose-treated subjects taking codeine showed retrograde movements of one or more of the 5-mm particles. This is certainly an underestimate, since the particles were not uniquely identified and so only net movements could be assessed. However, with this proviso, 17 retrograde movements were recorded in the lactulose-treated subjects, but only 10 were recorded in the lactulose-treated subjects taking codeine. Effect of Particle Size. There were no significant differences in the behavior of the 0.2-mm compared with the 5-mm particles within the colon. Mean transit times through the ascending colon were not significantly different, nor did the effect of codeine differ according to particle size.
Our technique of delivering radioisotope as a bolus to the ileocecal region avoids many of the problems associated with orocecal intubation studies of colonic transit (7, 8). It is significantly less stressful to the patient, technically easier to perform, and does not require the presence of a tube, which significantly accelerates small bowel transit (9). Since we required no special diet or drug administration, our results are more likely to be representative of normal physiological behavior. Our Digestive Diseases and Sciences. Vol. 38. No. 6 (June 1993)
ANTIDIARRHEAL ACTIONS OF CODEINE method also provides high-quality images by avoiding small intestinal dispersion, which results if the radionuclide is given unencapsulatcd by mouth. The arrival of radioactivity in the colon and its subsequent progress is easily defined with this technique, assisted by the presence of the hepatic marker, allowing alignment of sequential scintigraphic images. The main drawback of the method is the occasional rupture of the capsules in the terminal ileum and subsequent release of a portion of the radioisotope, which can be seen to trail back into the small intestine. This has the effect of giving a reduced percentage recovery of radioisotope counted in the colon at that particular acquisition time. A further source of error is the changes in the regions of interest due to changes in colonic shape occurring during the study. We believe, however, that these disadvantages are easily outweighed by the significant advances already mentioned, and other groups have recently developed similar methods with equally encouraging results (10). We have shown in this study that lactulose 20 ml thrice daily effectively doubled stool frequency and, as expected, reduced mean transit time through the ascending colon, which at 5.3 ± 2.5 hr, (N = 11) was approximately half that previously observed (4) in healthy untreated subjects at 12.9 ± 3.7 hr, (N = 11, P < 0.001) using an identical protocol (4). Codeine in normal clinically effective doses (30 mg four times daily) successfully decelerated colonic transit and returned stool frequency to normal in lactulose-treated subjects. Codeine also exerted a marked effect on mouth-terminal ileum transit, delaying it by approximately 2 hr. Previous intubated studies have shown similar effects, mainly due to a delay in small bowel transit (3), although, like other opiates, codeine may also delay gastric emptying (11). This delay in mouth-cecum transit would be expected to smooth out the fluctuations in ileocolonic inflow seen postprandially. Previous studies have clearly shown that the capacity of the colon to absorb fluid and electrolytes is prodigious (up to 6 liters/24 hr) provided that the inflow is at a uniform low rate of l-4ml/min (12). However, sudden boluses of fluid, such as might be seen postprandially after ingestion of malabsorbed sugars such as mannitol (13), lactose in hypolactasia (14), and presumably also lactulose, probably overwhelms the absorptive capacity of the ascending colon. This is probably due to sudden distension, which elicits mass movements, dramatically reducing mucosal contact time and hence absorption (12). Our obscrDigeslive Diseases and Sciences, Vol. 38, No. 6 Uune 1993)
vation that codeine reduces the apparent effect of a meal could be due to delay in the arrival of lactulose and meal residue or to a direct effect on the colonic response to eating. The fact that the effect is clearly demonstrated within 2 hr postprandially is somewhat in favor of a direct effect of codeine in reducing mass movements within the ascending colon, since we know from previous (unpublished) studies using similar meals that meal residue rarely reaches the colon much before 2 hr after the meal. Our findings, which relate to a conventional dosing regimen, do not allow us to extrapolate to much higher doses that arc sometimes necessary. Colonic scintigraphy recently has been used to show a similar effect of morphine on colon transit in normal subjects with an acceleration of transit by a u. receptor antagonist (15), implying some tonic activity in the endogenous opiate pathways. We have shown that codeine reduced the number of retrograde movements observed. Other gamma scintigraphic studies of colonic movements have reported that while diarrheal states are characterized by increased retrograde as well as antegrade movements, both types of movements are much less common in normals or those suffering from constipation (16). It may be that in diarrheal states the increased fluidity of colonic contents allows greater movements in all directions. Opiates are known to enhance water and electrolyte absorption (17), which we presume would increase the viscosity of colonic contents and thus nonselectively reduce both antegrade and retrograde movements. Alternatively, opiate receptor stimulation may so increase segmental, nonpropulsive, contractions that transit is reduced in both directions. Several animal (18, 19) and human (20) studies have reported increased frequency of phase Ill-like activity after loperamide and morphine during fasting, associated with a delayed small bowel transit. Opiates also have direct actions on the colonic muscle; high doses of codeine selectively increase canine colonic circular muscle activity while they decrease longitudinal muscle activity, a pattern that would also be expected to delay transit (21). Human studies done many years ago using balloon pressure transducers also showed a reduction in propulsive contractions with an increase in nonpropulsive contractions (22), while more recent studies show that morphine abolishes prolonged propagated contractions induced by cecal infusion of oleic acid (23). Recent use of the barostat in the canine colon to assess tone has shown that morphine increases tone and contrac-
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BARROW ET AL tion rate (24). When taken with our findings, these data point to an increase in nonpropulsive and a decrease in propulsive activity as a consistent feature of opiates on the human and canine colon. We could detect no differences in the rate of transit between 0.2-mm and 5-mm particles, although this probably spans the complete range of particle sizes likely to enter the colon from food residue. This agrees with other studies (25) that have likewise found no differences in transit times of liquid compared with 1.0-mm markers. While lactulose, like other nonabsorbable small molecules, increases ileocolonic inflow, this is probably not its only effect since it is rapidly metabolized to short-chain fatty acids (26) including some, such as lactic acid, that arc likely to stimulate the colon (27). Morphine, which, like codeine, acts predominantly at u. receptors, has previously (23) been shown to be capable of inhibiting the propulsive response of the colon to oleic acid infusion (28). We believe that this makes it likely that codeine similarly reduces the propulsive movements that occur in the ascending colon in the immediate postprandial period in subjects taking clinically effective doses of lactulose. Patients suffering from diarrhea often experience urgent defecation soon after meals, no doubt due to an exaggerated movement of liquid stool from the proximal to the distal colon. Our studies have shown that codeine is of benefit in reducing this movement in osmotic diarrhea, but caution is needed before extrapolating our findings to other types of diarrhea in which opiates may exert different effects. Lactulose treatment combined with gamma scintigraphy provides a simple experimental model for osmotic diarrhea that could usefully be applied to evaluate other, newer, antidiarrheal agents.
5. 6. 7.
8. 9.
10.
11. 12. 13. 14. 15.
16.
17. 18.
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ANTIDIARRHEAL ACTIONS OF CODEINE meisier AR: Colonic capacitance and transit in man: Modulation by luminal contents and dnigs. Gut 31(4):443-449, 1990 24. Ncri M, Phillips SF, Fich A: Measurement of lone in the canine proximal colon. Gastroenterology 96:A364, 1989 25. Proano M, Camilleri M, Phillips SF, Thomforde GM, Brown ML, Tucker RL: Unprepared human colon does not discriminate between solids and liquids. Am J Physiol 260:G13G16, 1991 26. Florcnt C, Flour ie B, Leblond A, Rautureau M, Bernier J-J, Rambaud J-C: Influence of chronic lactulose ingestion on the
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colonic metabolism of lactulose in man (an in vivo study). J Clin Invest 75:608-613, 1985 27. Bennett A, Elcy KG: Intestinal pH and propulsion: an explanation of diarrhoea in lactase deficiency and taxation by lactulose. J Pharm Pharmacol 28:192-195, 1976 28. Spiller RC, Brown ML, Phillips SF: Decreased fluid tolerance, accelerated transit, and abnormal motility of the human colon induced by oleic acid. Gastroenterology 91:100107, 1986
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