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Keywords:

  • colonic motility;
  • colonic transit time;
  • nicotine;
  • radio-opaque marker technique

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

The radio-opaque marker technique (ROMT) is a safe and noninvasive method to determine total colonic (TCTT) and segmental colonic transit times (SCTT). Previous results have shown that smoking volunteers had significantly longer TCTT than nonsmokers, but the underlying mechanism was not clear. We investigated the effect of transdermal nicotine application in two different doses in a nonblind randomized experiment involving three distinct phases. In phase 1 baseline transit times were determined with an abdominal X-ray after a 6-day period of marker ingestion and again after the following bowel movement to study the influence of a bowel movement just before the X-ray. TCTT was nearly twice as high before than after defaecation (42.6 h vs. 25.1 h, P < 0.05). The main acceleration was found in the rectosigmoid (RS) (18.6 h vs 7.1 h, P < 0.05) with no significant changes in right (RC) and left colon (LC). In phase 2 and 3 nicotine was applied in two doses of 17.5 mg day−1 and 35 mg day−1 in random order. Both doses resulted in a significant decrease of TCTT compared to the predefaecation baseline (42.6 h vs 32.2 h/28.2 h, respectively, P < 0.05). Again the main effect was located in the RS (18.6 h vs 9.9 h/7.6 h, P < 0.05). Short-term application nicotine results in a decrease of TCTT which is due to an accelerated transit in the RS.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

The physiology of gastrointestinal motility, though the subject of intense study, still has many unknown variables in gastrointestinal research. A growing number of neuronal and hormonal transmitters are being discovered, but the complex details of how gastrointestinal motility is coordinated as well as the roles of the individual substances involved have yet to be fully elucidated.1–3

Several methods, invasive and noninvasive, like hydrogen exhalation tests, small-bowel manometry and measurement of segmental (SCTT) and total colonic transit times (TCTT), are being employed in vivo to assess quantitatively motility-related parameters.4

A simple and noninvasive technique for the measurement of segmental and total colonic transit times is based on radio-opaque markers (ROMs) and a plain abdominal X-ray, as described and standardized by Metcalf and Chaussade5–8 and satisfactorily applied by various other authors.9–12

Along the same line of investigations, we have previously undertaken a large trial to establish standard values for SCTT and TCTT in the Swiss population. In this investigation we have observed that TCTT is influenced by gender, hormonal status and smoking habits.11,12 Furthermore it became clear that TCTT was significantly longer in male smoking volunteers than in nonsmoking controls,11,12 which seems to contradict the popular belief that smoking can be helpful to initiate a bowel movement. The mechanism by which these phenomena have to be explained, however, is not clear. Because cigarette smoke contains many pharmacologically active substances,13,14 we had to limit our intentions. Therefore, we focused our interest on one ingredient, nicotine.

Only a few studies are available in which the effect of nicotine on the colon15–19 has been investigated. We aimed therefore to assess further the effect of the ganglionic substance nicotine on SCTT and TCTT by administering the compound in two standardized doses to nonsmoking volunteers.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

Participants

The study was performed in 22 healthy male volunteers recruited from the medical and supporting hospital staff and from a group of volunteers who had answered a public notice. The participants were nonsmokers aged 22–55 years (mean age 35). None of the participants had smoked in the 5 years preceding the study, and none had a history of abdominal surgery. All participants had normal bowel habits without a history of constipation. No participant had ever taken laxatives or was taking any other medication at the time of inclusion. There was no history of colorectal disease, heart or lung disease nor any other chronic disease. All participants underwent a complete physical examination and had to fill out a questionnaire concerning their personal medical and drug history. Written informed consent was obtained from all participants. The study was approved by the Ethic Committee of the University of Basel.

Radio-opaque marker technique

Ten radio-opaque markers in a gelatine capsule were ingested over six consecutive days at exactly the same time in the morning. A plain abdominal X-ray was taken in supine position 24 h after ingestion of the last capsule. Colonic transit times were calculated according to previously described methods.5–8 Multiplying the number of visible markers on the film by 2.4 yields the colonic transit time in hours for total and segmental transit times. For calculation of SCTTs the colon is divided in three segments (right colon = RC, left colon = LC, rectosigmoid = RS) by drawing three lines originating from the spinal process of the fifth lumbar on the film. By general agreement the RC is the area between the vertical line lying over all the spinal processus and the one to the right femoral head. The LC is the area between the vertical line and the line to the left femoral head. The RS is the area between both lines to the femoral heads (see Fig. 1). Markers are made according to FDA standards containing polyurethane with a barium sulphate coating. They have different forms for each day in order to facilitate compliance assessment. The markers were purchased from P + A Mauch, Muenchenstein, Switzerland. They carry no pharmacological properties, they do not alter motility or transit and they are excreted in the faeces.

image

Figure 1. Illustration of the radio-opaque marker technique in determining colonic transit times: three lines are drawn originating from the processus spinosus of L5. The colon is subdivided into the right colon, left colon and rectosimoid accordingly.

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Study design

The study was carried out as an open randomized nonblind trial and consisted of three phases.

Phase 1  Measurement of SCTT and TCTT without application of nicotine (baseline study). Radio-opaque markers were given over a period of 6 days and transit was assessed as described before. A second X-ray was taken immediately after the following defaecation, and colonic transit times were determined again. This was done to study the influence of a bowel movement on colonic transit time before the X-ray.

Phases 2 and 3. SCTT and TCTT were measured after nicotine administration given at a dose of either 17.5 mg day−1 or 35 mg day−1 as transdermal system over a period of 8 days. The order of the doses was randomized. After the baseline measurement and between the applications of the two nicotine doses a washout phase of at least 1 week was included (see Fig. 2).

image

Figure 2. Flow chart of the randomized study to evaluate the effects of transdermally administered nicotine on colonic transit times. Phase I: measurement of baseline values. Phases II and III: administration of 17.5 or 35 mg nicotine day−1 in random order. The washout time was at least 1 week in between.

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Transdermal nicotine appliction

Nicotinell-TTS® nicotine patches were manufactured by Ciba Geigy, Basel, Switzerland, and are available in several doses. They are typically used for assistance in smoking cessation. These patches were placed on the skin over the gluteal muscles or any other area of the body with sufficient hairless surface to provide reliable adhesion. For reasons of convenience and compliance the patches were applied and changed every 24 h at the time of marker ingestion.

Diaries

Each participant had to record the following parameters during each phase of the study: number and composition of meals, fluid intake, amount of coffee and tea consumed, stool frequency, stool consistency, exact time of X-ray and interval between X-ray and last bowel movement. In addition, every participant quantitatively recorded the composition of his nutrition over three typical days. From these records fibre content and caloric intake were estimated.

Statistical analysis

Results of colonic transit times are reported as means and medians of measured transit times in hours and SD. The individual values were compared by means of the Friedman test. P = 0.05 was used as the limit of statistical significance. For statistical analysis the predefaecation baseline parameters were used. One participant had to be excluded from the analysis as he failed to record a detailed diary. One of the participants left the study in phase 3 of the experiment because of nausea after nicotine administration. Therefore, we report the results of the remaining subjects (n = 20).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

Colonic transit times: baseline measurements

We found TCTTs with a mean (median) of 42.6 ± 4.6 (39.6) h after the first X-ray (Fig. 3a). The means (medians) for RC, LC and RS were 8 ± 2.2 (9.6) h, 11.4 ± 2.8 h (9.6) and 18.6 ± 3.5 (13.2) h, respectively (Fig. 3b).

image

Figure 3. Total (a) and segmental colonic transit time (b) as measured by the radio-opaque marker technique at baseline and after transdermal application of two different doses of nicotine. TCTT = colonic transit time. RC = right colon. LC = left colon. RS = rectosigmoid. N1 = phase 1: application of 17.5 mg nicotine day−1. N2 = phase 2: application of 35 mg nicotine day−1. *< 0.05.

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Colonic transit times before and after application of nicotine

Measurements of transit times before and after application of two doses of nicotine both yielded a decrease in TCTT, which was shortened by 20% and 32% as compared to predefaecation baseline values (17.5 mg nicotine day−1 and 35 mg nicotine day−1, respectively). After 17.5 mg nicotine day−1 and 35 mg nicotine day−1 the means (medians) were 32.2 ± 3.7 (30 ) h and 28.2 ± 4.1 (27.6) h, respectively (< 0.05). Transdermal application of nicotine resulted in a significantly lower TCTT (Fig. 3a). This effect was not due to changes in the RC and LC, which were only minor and insignificant. A major decrease in SCTT could only be seen in the RS, with a decrease of 47%/60%, respectively, compared to baseline values. Baseline mean (median) in the RS was 18.6 ± 3.5 (13.2) h. After 17.5 mg nicotine day−1 and 35 mg nicotine day−1 the means (medians) were 9.9 ± 1.7 (9.6) h and 7.6 ± 2.4 (3.6) h (< 0.05). The results are shown in Fig. 3(b).

Colonic transit times before and after defaecation

Baseline measurements before and shortly after defaecation were distinctly different. TCTT after defaecation was shortened by 41% as compared to the first baseline measurement. P values are reported as a descriptive p value [ ] because it is evident that transit times decrease when markers are excreted. The mean (median) TCTT after the bowel movement was reduced to 25.1 ± 3.6 (22.8) h [< 0.05]. The main effect occurred in the left colon (35% reduction) and rectosigmoid (72% reduction). Means (medians) before and after defaecation in LC: 11.4 ± 2.8 (9.6) h/7.4 ± 2.0 (4.8) h and RS: 18.6 ± 3.5 (13.2) h/7.1 ± 1.8 (3.6) h [< 0.05]. These results are shown in Fig. 4.

image

Figure 4. Total (a) and segmental colonic transit times (b) as measured by the radio-opaque marker technique in 20 healthy nonsmoking volunteers before and after bowel movement. RC = right colon. LC = left colon. RS = rectosigmoid. TCTT = total colonic transit time. Pre = before bowel movement. Post = after bowel movement. *< 0.05.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

The present study has shown that short-term transdermal application of nicotine patches exerts measurable effects on colonic transit times as quantified by the radio-opaque marker method. Transit times measured at baseline were within the ranges observed in a different healthy population previously examined in other studies (Table 1).5–9,11,12,36 A dose-dependent, significant decrease of total colonic transit time was observed when nicotine was administered in two doses of 17.5 mg day−1 and 35 mg day−1.

Table 1.  Normal values for TCTT (means ± SEM). Thumbnail image of

The major difference responsible for this decrease in TCTT was a significant acceleration of transit through the rectosigmoid region. Changes in the left colon were not significant and the results in the right colon did not show any pattern.

Furthermore, this study shows that time intervals between the last defaecation and the abdominal X-ray influence the value for CTT when using the ROMT.

Various previous publications have described the effects of nicotine on the upper gastrointestinal tract20–28 and on mouth–caecum transit.29 While the pharmacodynamics of nicotine administration are well documented30–34 this study is among the first to examine the effects of nicotine on the motility of the lower gastrointestinal tract in humans. To our knowledge only one human in-vivo experiment has been carried out so far while there is ample information available on animal experiments.15–19 Nicotine is probably the most interesting component of roughly 4000 different substances in cigarette smoke. It is known that nicotine causes activation of the sympathetic neurone system, which can be blocked again after further dose increases. Tolerance and tachphylactic phenomena have also been described.1–3,35 Both adrenergic as well as cholinergic systems in the gastrointestinal tract are activated by nicotine. The response seems to be dependent on the ratio of receptor types present in the segment in question. With a predominantly sympathetic innervation of the colon, the expected effect of nicotine should be a decrease in motor activity.1 From investigators in diarrhoea research we know that relaxation of colonic segments can cause accelerated transit. We did not measure motor activity directly but our results suggest that the acceleration in the rectosigmoid can partly be explained by a decreased motor activity. Jameson et al. found profound changes in colonic motility after cigarette smoking. A biphasic action of nicotine was noted which resulted in a decrease of intracolonic pressure.19 These results seem to provide an idea of how nicotine may act in the colon. However, explanations on a neuronal level remain hypothetical because more research is needed to explain possible effects and interactions with other neurotransmitters, such as substance P, VIP and NO.

The importance of recording the times of bowel movement and abdominal X-ray when using the ROMT is illustrated by our results of TCTT and SCTT before and immediately after defaecation. Total colonic transit times at baseline were in the upper normal range and significantly shortened after defaecation. This can be explained by the expulsion of a high number of markers in the faeces from the rectosigmoid. When the ROM technique is used to determine colonic transit times, the time interval between the last bowel movement and the abdominal X-ray should be recorded and must be taken into consideration in clinical trials. This has not previously been mentioned in trials using the ROM technique.

There are several questions which remain unexplained. One is the observation of a prolonged overall transit in smokers compared to nonsmokers, in contrast to the present results and to personal experiences of smokers (bowel movement is facilitated by a morning cigarette). A possible explanation follows the line of pharmacological effects of nicotine on the gut with tolerance or reversal of effects through tachyphylaxia. In addition, it cannot be excluded that active ingredients of tobacco smoke other than nicotine are responsible. Finally, we cannot exclude that the prolonged transit in smokers is not pharmacological, but that different habits and lifestyle of smokers are responsible for the observed effects.

ACKNOWLEDGMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References

We thank Dr R. Brignoli for carrying out part of the statistical analysis and also Ciba-Geigy for providing all nicotine patches.

References

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENTS
  8. References
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