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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Acute administration of octreotide reduces visceral perception and therefore has been suggested as potential treatment for irritable bowel syndrome. Whether prolonged treatment with octreotide also reduces visceral sensitivity and improves gastrointestinal symptoms remains, however, unknown.

Aim  To investigate the effect of a slow release preparation of octreotide on rectal sensitivity and symptoms in irritable bowel syndrome patients.

Methods  Forty-six non-constipated irritable bowel syndrome patients (52% female, 19–63 years) participated. Before and after 8 weeks of treatment with octreotide (Sandostatin LAR 20 mg i.m.) or placebo, patients underwent a barostat study to assess the rectal sensitivity. During a 2-week run-in period and treatment, abdominal pain, defecation frequency, consistency and symptom relief were scored weekly.

Results  Octreotide, but not placebo, significantly increased the threshold for first sensation. Thresholds for urge to defecate and discomfort/pain and rectal compliance were not altered by either treatment. Octreotide improved stool consistency compared with placebo (loose stools after eight weeks: octreotide: 52%, placebo: 81%, < 0.05). In contrast, abdominal pain and defecation frequency were not affected.

Conclusions  Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve irritable bowel syndrome symptoms.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The irritable bowel syndrome (IBS) is the most common disorder seen in the gastroenterological out-patient practice, accounting for approximately 28% of all diagnoses.1 IBS is diagnosed on the basis of a series of clinical symptoms in the absence of organic diseases. These symptoms consist of chronic abdominal pain or discomfort, associated with altered defecation and changes in bowel habit. Symptom subgroups of IBS can be distinguished based on the predominant bowel habit, i.e. constipation predominant IBS (IBS-C), diarrhoea predominant IBS (IBS-D) and IBS with alternating constipation and diarrhoea (IBS-A). Several studies have shown that IBS patients exhibit enhanced perceptual responses to controlled distension of the colon and rectosigmoid.2–5 This so-called visceral hypersensitivity is a consistent finding in IBS and widely accepted as an important pathophysiological mechanism in generating IBS symptoms.6–9 Agents normalizing visceral sensation theoretically are potential new treatments for IBS.

One possible candidate drug is the somatostatin analogue octreotide. In acute experiments, administration of octreotide reduces perception of rectal and gastric distension in healthy volunteers10–13 and the perception of colonic and rectal distension in IBS patients.14–16 As such, octreotide may be useful to normalize hypersensitivity in IBS patients. Especially, as water and electrolyte absorption are increased and secretory diarrhoea is reduced by octreotide,17–20 octreotide may be an interesting drug to treat diarrhoea predominant and alternating type IBS. An early case report indeed suggests that long-term treatment with octreotide can provide relief in IBS symptoms.21 However, at present, no controlled data are available from long-term treatment of IBS with somatostatin analogues. Therefore, we evaluated the effect of Sandostatin LAR, a slow release preparation of octreotide used in the treatment of acromegaly on rectal visceral sensitivity and IBS symptoms in non-constipated IBS patients.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study subjects

Forty-six non-constipated IBS patients (52% female, mean age 38 ± 2 years, range: 19–63 years) were recruited between September 2002 and November 2004 from the gastrointestinal motility unit at the Academical Medical Centre, a tertiary referral centre. Selection criteria included a positive diagnosis by Rome II criteria of diarrhoea predominant or alternating type of IBS,22 excluding those with constipation predominant IBS. A minimum work-up to exclude organic disease included careful history taken, a normal physical examination, normal thyroid-stimulating hormone levels and blood counts, negative stool examinations and a normal flexible sigmoidoscopy. Biopsies of normal colonic tissue were routinely taken to exclude microscopic colitis. Patients had to be free of concomitant diseases (e.g. diabetes and cardiovascular disorders), including psychiatric disorders. Medication likely to interfere with gastrointestinal function or analgesics was discontinued at least 7 days before entering the study. The study protocol was approved by the Medical Ethics Committee of the Academic Medical Centre. All participants gave their written and informed consent to participate in the study. Basal rectal sensitivity in IBS patients is compared with a matched historical control group that underwent the same barostat protocol.3 This historical control group consists of 17 healthy volunteers (47% female, mean age 39 ± 4 years) and were recruited by public advertisement.

Study drug

Sandostatin LAR (Novartis Pharmaceuticals Corp., East Hanover, NJ, USA) is a microencapsulated octreotide acetate suspension and is prepared immediately before administration. A vial containing the powder with Sandostatin LAR is gently wetted with 5-mL diluent and moderately swirled for 30–60 s until a milky, uniform suspension is achieved. A 19-gauge needle is used to inject this suspension with a steady pressure intra-muscularly in the gluteal region. Serum octreotide levels rise from the end of the first week to a steady concentration, which is maintained to approximately 5-weeks postinjection.18

Study design

This study is a placebo-controlled, double-blind, randomized trial, consisting of a 2-week screening period followed by an 8-week treatment period. Patients were randomized 1:1 for either treatment with intra-muscular injections of octreotide 20 mg or placebo. Before and after the treatment period, a rectal barostat study was performed to assess rectal sensitivity and IBS-symptoms were scored every week.

Barostat studies

To assess the sensitivity to rectal distension, we used an electronic barostat that automatically corrected for the compressibility of air (Synetics Visceral Stimulator, Stockholm, Sweden) (Figure 1). The barostat was connected to a 500-ml polyethylene bag (maximal diameter 9 cm), tightly wrapped on the distal end of a double lumen polyvinyl tube (Salem Sump tube 14 Ch.; Sherwood Medical, St Louis, MO, USA) that was introduced in the rectum.3, 23

image

Figure 1.  Barostat protocol.

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Minimal distending pressure (MDP) was defined as the minimum pressure at which the intrabag volume was >30 mL. Subjects scored the perception of sensation evoked by rectal distension using a 6-point scale with verbal descriptors (0 = no sensation; 1 = first sensation; 2 = first urge to defecate; 3 = normal urge to defecate; 4 = severe urge to defecate; 5 = discomfort/pain). If a subject reported discomfort or pain, the bag was instantaneously deflated. For safety, the bag was automatically deflated at pressures above 50 mmHg or volumes above 600 mL.

Phasic distensions The first rectal distension series was performed according to a phasic, semi-randomly ascending isobaric distension protocol. The pressure increment was 3 mmHg above MDP (3, 6, 12, 9, 18, 15, 24, 21, 30 mmHg, etc.), each step lasting 2 min and separated by 1-min intervals at baseline (MDP). The inflation rate was set at 38 mL/s. Sensations were scored after 10, 60 and 150 s of each distension step. Sensation was determined as the highest score during each distension step, independently of timing.

Volume ramp distension Subsequently, after a 15-min recuperation period with the bag deflated, a second distension at a constant inflation rate of 40 mL/min was applied. Subjects were asked to report rectal sensation on the 6-point scale mentioned above.

Symptom assessment

During a 2-week run-in period and during treatment, abdominal pain was assessed by the validated Subject’s Global Assessment (SGA) of Abdominal Pain and Discomfort which consists of a 100-mm visual analogue scale with severity descriptors (absent, very mild, mild, moderate, severe and very severe).24

During the treatment period, weekly symptom relief was monitored by the SGA of relief with the following question: compared with the way you felt before entering the study, how would you rate your relief of symptoms during the past week? Possible answers were completely relieved, considerably relieved, somewhat relieved, unchanged or worse.24

The severity of IBS symptoms of diarrhoea, abdominal bloating, flatulence, urgency and the feeling of incomplete evacuation was scored before and after 8 weeks of treatment with the validated Gastrointestinal Symptom Rating Scale, in which the intensities of the symptoms are scored on a 7-graded Likert scale, with descriptive anchors (0 = no symptoms at all; 1 = minimal symptoms; 2 = mild symptoms; 3 = moderate symptoms; 4 = rather serious symptoms; 5 = serious symptoms and 6 = very severe symptoms).25

Data analysis

The primary endpoint was the effect of octreotide on the rectal sensitivity during rectal distension. Secondary endpoints were rectal compliance, global symptom relief, abdominal pain scores and gastrointestinal symptoms.

Rectal compliance was calculated as the slope of the steepest part of the pressure–volume curve during phasic distension, obtained by measuring the mean intrabag volumes over the last 60 s of the first four distension steps and plotting it against the corresponding distending pressure.23, 26

Patients were classified as responder when they reported at least 50% of their weekly SGA of relief assessments as either considerably relieved or completely relieved or 100% at least somewhat relieved.24 The definition of responder in the SGA of abdominal pain and discomfort was a reduction in mean visual analogue scale score of 40%.24 Furthermore, symptom relief is expressed by a weekly percentage of patients reporting some degree of (somewhat to complete) relief of symptoms.

As the expected effect of octreotide on visceral perception would be more pronounced in patients with lower sensory thresholds, we performed a post hoc analysis to compare patients with a lower sensory thresholds, or visceral hypersensitivity, to patients with normal rectal sensitivity.

Statistics

The primary endpoint was the threshold for discomfort/pain during rectal distension. Based on the data derived from a previous study,3 we assumed a relevant detectable difference would be 10 mmHg with a common s.d. of 11 mmHg, which is the increase in thresholds needed for IBS-patients to achieve the same level as healthy volunteers. A two group t-test with a 0.050 two-sided significance level will have 80% power to detect a difference in means of 10 mmHg, with a common s.d. of 11 mmHg, when the sample sizes in each group is 21. To compensate for potential dropouts, we invited a total of 46 patients to participate in this study protocol.

Statistical evaluations were performed by using commercially available software (spss 12.0.1; SPSS Inc. Chicago, IL, USA). Continuous data were compared by using the Student t-test for independent samples and the paired t-test for related samples. Nominal data were compared by the Mann–Whitney U-test for independent samples or the Wilcoxon signed rank test for related samples. Comparison of proportion was performed by using chi-squared testing. Differences were considered significant at the 5% level. Data are shown in mean ± SEM.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study subjects

Table 1 summarizes the demographic characteristics of IBS-patients and the historical control group (healthy volunteers: HV). All participants were Caucasian. Based on their clinical history, 76% of the IBS-patients were considered as having diarrhoea predominant and 24% alternating type of IBS. The mean duration of symptoms at intake was 9.7 ± 1.8 years (range: 0.8–58.0 years). During the treatment period, two participants, both receiving placebo, experienced an increase in abdominal pain and therefore dropped out before finishing the study protocol. Apart from a brief, self-limiting, tenderness at the injection site (in both placebo and octreotide), treatment was well tolerated and no side effects other than IBS symptoms were mentioned.

Table 1.   Baseline characteristics
 HV†IBS AllPlaceboOctreotide
  1. IBS, irritable bowel syndrome; HV, healthy volunteers (historical control group); IBS-D, diarrhoea dominant IBS.

  2. Data are shown in mean ± SEM.

  3. †Adapted from Kuiken et al3.

n17462323
Male:female9:8 (47% F)22:24 (52% F)13:10 (43% F)9:14 (61% F)
Age (years) range39 ± 4 (19–62)38 ± 2 (19–63)40 ± 3 (20–59)37 ± 3 (19–63)
% IBS-D767078
Duration of symptoms (years)9.7 ± 1.89.4 ± 1.89.9 ± 3.1

Rectal sensitivity at baseline

Pressure sensitivity In IBS patients, the baseline mean MDP level (7.4 ± 0.4 mmHg) did not differ from historical data obtained in healthy volunteers (HV, MDP: 6.3 ±  0.7 mmHg)3. The mean thresholds for first sensation (2.5 ± 0.3 mmHg), urge (6.9 ± 0.5 mmHg) and discomfort (21.0 ± 1.6 mmHg) were all significantly lower than those of healthy volunteers (5.1 ± 1.0, 12.9 ± 1.3 and 34.8 ± 3.0 mmHg, respectively) (< 0.01)

Using the 5th percentile of the discomfort thresholds measured in HV (18 mmHg)3 as cut-off, 30 patients (19 female and 11 male, mean age: 37 ± 2 years) were considered hypersensitive to rectal distension (Figure 2).

image

Figure 2.  Baseline thresholds for discomfort in mmHg above minimal distending pressure. Mean threshold in healthy volunteers (HV): 35 ± 3 mmHg, irritable bowel syndrome (IBS) 21 ± 2 mmHg. *< 0,001 vs. HV. The upper limit of hypersensitivity is, based on the 5th percentile of HV, defined at 18 mmHg. Of all IBS patients, 30 (65%) were therefore considered to have a hypersensitive rectum. †Adapted from Kuiken et al.3

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Volume sensitivity During volume-ramp distension, the thresholds in IBS for first sensation, urge and discomfort (55 ± 9; 152 ± 14 and 243 ± 14 mL, respectively) were all statistically lower than those in HV (95 ± 23. 212 ± 24 and 328 ± 20 mL, respectively; < 0.01).

Rectal compliance The slope of the steepest part of the pressure–volume curve during phasic distension in healthy volunteers was 14 ± 1 mL/mmHg, which was comparable in IBS patients (13 ± 1 mL/mmHg).

Effect of octreotide in IBS patients:

Rectal sensitivity
Pressure sensitivity

Minimal distending pressure levels were not affected by either of the treatment modalities (placebo: before 8.1 ± 0.6, after 7.8 ± 0.7 mmHg and octreotide: before 7.0 ± 0.7, after 7.2 ± 0.6 mmHg). Octreotide, but not placebo, significantly increased the pressure sensitivity threshold for first perception. After treatment with octreotide, the mean threshold of first sensation increased from 1.7 ± 0.3 to 3.3 ± 0.4 mmHg above MDP (< 0.01), whereas placebo had no effect (3.4 ± 0.4 vs. 3.6 ± 0.4 mmHg). In contrast, the thresholds for urge or discomfort were not affected by placebo (urge: from 7.4 ± 0.8 to 8.1 ± 1.0 mmHg, discomfort: from 21.9 ± 2.5 to 21.4 ± 1.9 mmHg) or octreotide (urge: from 6.5 ± 0.6 to 8.7 ± 1.4 mmHg, discomfort: from 19.7 ± 2.3 to 17.5 ± 2.5 mmHg) (Figure 3).

image

Figure 3.  Effect of placebo and octreotide on rectal sensory thresholds for first sensation, urge and discomfort, before and after 8 weeks of treatment in mmHg above minimal distending pressure. Data are expressed as mean + SEM. *< 0.001.

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Volume sensitivity

As in pressure-controlled distension, volume thresholds showed a significant increase in mean volume at first sensation during octreotide treatment (44 ± 10 to 77 ± 16 mL, < 0.01), but not during placebo (67 ± 14 to 66 ± 14 mL). No differences were found in threshold for sensation of urge or discomfort in placebo (urge: from 169 ± 20 to 183 ± 20 mL, discomfort: 272 ± 22, after 286 ± 21 mL) or octreotide (urge: from 136 ± 19 to146 ± 20, discomfort: from 216 ± 17 to 220 ± 22 mL).

Rectal compliance

Rectal compliance was not affected by octreotide or placebo. At baseline, compliance was 14 ± 1 and 12 ± 1 mL/mmHg, respectively, in the groups receiving placebo and octreotide. The compliance measured after 8 weeks of treatment, with placebo or octreotide (placebo: 15 ± 1 mL/mmHg and octreotide: 14 ± 1 mL/mmHg), was not different from baseline values.

Hypersensitive vs. normosensitive

Patients with visceral hypersensitivity and patients with normal sensitivity may represent different subpopulations and may respond differently to pharmacologic interventions, especially when targeting visceral sensation. Therefore, we performed a post hoc analysis to compare the effect of octreotide on rectal sensitivity in hypersensitive vs. normosensitive IBS patients.

Pressure sensitivity

Both hypersensitive and normosensitive patients showed a small but significant increase in threshold for first sensation after treatment with octreotide (hypersensitive: 1.4 ± 0.4 to 2.7 ± 0.4 mmHg, <0.01; normosensitive 2.7 ± 0.3 to 5.0 ± 0.6 mmHg, < 0.05) whereas no alterations were observed when treated with placebo (hypersensitive: 3.0 ± 0.6 to 2.8 ± 0.2 mmHg; normosensitive 4.1 ± 0.5 to 4.9 ± 0.8 mmHg) (Figure 4). At baseline, the thresholds for discomfort/pain were comparable in the patient groups. However, octreotide did not significantly alter the mean threshold of discomfort/pain compared with placebo, neither in hypersensitive (13.4 ± 2.4 vs. 16.6 ± 1.5 mmHg) nor in normosensitive (29.3 ± 2.4 vs. 29.0 ± 4.3 mmHg) patients (Figure 5).

image

Figure 4.  Individual thresholds for first sensation during rectal distension, before and after 8 weeks of treatment with placebo or octreotide. (a) hypersensitive and (b) normosensitive patients. *< 0.01, **< 0.05, compared to before treatment.

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image

Figure 5.  Individual thresholds for discomfort/pain during rectal distension, before and after 8 weeks of treatment with placebo or octreotide. (a) hypersensitive and (b) normosensitive patients.

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Volume sensitivity

In hypersensitive patients, mean intrabag volume of first sensation was 52 ± 12 mL before, and 45 ± 8 mL after placebo, vs. 28 ± 7 mL and 53 ± 10 mL (NS, = 0,05) with octreotide, respectively. When treated with placebo, the volume of first sensation in normosensitive patients was 90 ± 30 mL before and 101 ± 32 mL after treatment, compared with octreotide, before 89 ± 30 mL and after 147 ± 45 mL (NS). At baseline, the threshold for discomfort/pain measured during volume ramp distension was significantly higher in hypersensitive patients treated with placebo compared with those treated with octreotide (237 ± 24 mL and 182 ± 12, respectively < 0.05). However, 8 weeks of treatment with octreotide or placebo did not alter these thresholds (placebo 252 ± 24 mL, octreotide 185 ± 21 mL). In the normosensitive patient, baseline values were comparable and likewise, no differences were found after treatment with placebo (before: 330 ± 37 mL, after: 341 ± 31 mL, respectively) or octreotide (before: 313 ± 29 mL, after: 318 ± 37 mL).

Rectal compliance

Compliance was comparable between patients receiving placebo or octreotide, before treatment (hypersensitive 13 ± 1and 12 ± 1 mL/mmHg, respectively: normosensitive 16 ± 2 and 15 ± 1, respectively) and was not significantly altered by either of the treatment modalities (hypersensitive 15 ± 2 and 14 ± 2 mL/mmHg, respectively: normosensitive 16 ± 2 and 14 ± 1, respectively).

Symptoms

Global relief

Figure 6 shows the weekly percentage of patients reporting some degree of (somewhat to complete) relief of symptoms. The percentage of patients experiencing symptom improvement was statistically not different between the two treatment groups. According to the criteria of Muller-Lissner et al.24 (at least 50% of the weekly SGA of Relief assessments as either considerably relieved or completely relieved or 100% at least somewhat relieved), one patient is considered responder in the placebo group (= 23) compared with four in octreotide (= 23), which is not significantly different.

image

Figure 6.  Weekly effect of placebo and octreotide on global symptom relief (SGA of relief), percentage of patients reporting some to complete relief of symptoms.

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Abdominal pain

The mean VAS-scores during screening were comparable between placebo and octreotide treated patients (placebo: 60 ± 4; octreotide 57 ± 4, NS). Treatment with placebo or octreotide did not significantly affect this VAS score of abdominal pain (placebo: 54 ± 4; octreotide: 55 ± 5, NS). After 8 weeks of treatment, one patient was considered a responder (at least 40% reduction in VAS-score) in the placebo-group vs. two patients in the octreotide group (not significant).

Faecal consistency and frequency

Faecal consistency improved significantly during treatment with octreotide. After 8 weeks, the percentage of patients reporting at least moderate complaints of loose stools decreased from 91% to 81% when treated with placebo and from 78% to 52% with octreotide (< 0.05) (Figure 7).

image

Figure 7.  Percentage of patients reporting at least moderate complaints of loose stools at day 1 and after 8 weeks of treatment. *< 0.05.

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On the other hand, defecation frequency was not significantly affected by octreotide. The percentage of patients reporting at least moderate complaints of frequent defecation decreased from 91% to 76% with placebo and from 78% to 57% with octreotide (NS) (Figure 8).

image

Figure 8.  Percentage of patients reporting at least moderate complaints of other irritable bowel syndrome symptoms, obtained by Gastrointestinal Symptom Rating Scale questionnaire. Comparing placebo and octreotide (a) before and (b) after treatment. freq. def, frequent defecation; inc. evac, incomplete evacuation.

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Gastrointestinal symptoms

Other IBS symptoms did not improve significantly during treatment with octreotide or placebo (Figure 8). Before treatment, the percentage of patients reporting at least moderate complaints of flatulence (placebo 91%; octreotide 70%), bloating (placebo 86%; octreotide 87%), urgency (placebo 76%; octreotide 78%) and the feeling of incomplete evacuation (placebo 86%; octreotide 74%) was comparable between the two treatment groups. At the end of treatment, no significant differences were found in the percentage of patients complaining of flatulence (placebo 76%; octreotide 74%), bloating (placebo 76%; octreotide 65%), urgency (placebo 57%; octreotide 65%) or the feeling of incomplete evacuation (placebo 67%; octreotide 57%).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Somatostatin is a peptide hormone with a wide range of activity in the gastrointestinal tract: it inhibits intestinal motility, gastric exocrine and endocrine function, and absorption of nutrients and ions.27 These effects are mediated by somatostatin receptors (SSTR), of which currently five different subtypes have been cloned (SSTR1 to SSTR5).28, 29 The expression of SSTR varies enormously in the gastrointestinal tract. For example, all subtypes are expressed in the stomach, whereas in rodents SSTR1 and SSTR5 are found in the small intestines. In human, SSTR2 is expressed in the small intestine and is also found in colon and rectum.30 Mainly based on its anti-secretory effect, octreotide is currently used as treatment of severe diarrhoea. Recent evidence, however, demonstrates that SSTR may also be involved in viscero-perception. In the brain, including in those areas involved in visceral perception, all five receptor subtypes are expressed. In human, epidural administration of somatostatin produces a significant reduction in post-operative pain.31 Similarly, in rats, Carlton et al.32 demonstrated a reduction of capsaicin-induced pain behaviour following administration of somatostatin, most likely by SSTR2 on neurons in the dorsal root ganglia.

The somatostatin analogue octreotide, which has a high affinity for SSTR2 and SSTR5, has also been shown to have viscerosensory properties. In healthy subjects, octreotide reduces the perception of non-noxious gastrointestinal distensions. However, discomfort or pain was not significantly altered by octreotide.10, 12, 33 In contrast, in IBS patients, octreotide has an analgesic effect, as illustrated by an increased rectal threshold of discomfort and pain directly after i.v. or s.c. administration.14–16 Based on its visceral analgesic and anti-secretory effect, one might argue that somatostatin analogues could represent a potential new therapeutic approach for non-constipated IBS patients.

So far, studies have only reported on the acute effect of octreotide on visceroperception. However, before accepting octreotide as potential treatment, it is important to investigate whether prolonged administration with octreotide or related agents maintain their effect. This is particularly relevant as chronic administration of SSTR could result in receptor desensitization34. Therefore, in the current study, we evaluated the effect of prolonged treatment with octreotide in patients with non-constipated IBS. Sandostatin LAR is a long-acting slow release preparation of octreotide, used as treatment of acromegaly, gastroentero-pancreatic neuroendocrine tumours and carcinoid tumours. We showed that 8 weeks of treatment with octreotide decreased the sensation of non-noxious rectal stimuli or first sensation. However, no alteration was found in the thresholds of urge and discomfort or pain. Moreover, no effect on maximum tolerated volume or rectal wall compliance was observed, excluding an effect of octreotide on rectal tone. Previously, we demonstrated that patients with visceral hypersensitivity may respond differently to treatment compared with subjects with normal visceroperception.23, 35 Based on these findings, one might argue that especially patients with visceral hypersensitivity would react to octreotide. However, a post hoc analysis did not reveal a significant treatment effect in hypersensitive patients. Therefore, our data suggest that with the current dose, no significant effect on visceral perception (urge/discomfort) can be demonstrated. Similarly, in the current study population and with the current dose of octreotide, we were unable to show clinical improvement: global relief and symptoms of abdominal pain, bloating, flatulence, urgency or the feeling of incomplete evacuation did not improve after 8 weeks of treatment with octreotide. In contrast, stool consistency was significantly improved, a finding in line with its application as treatment of secretory diarrhoea of different aetiologies.20 Possible mechanisms mediating this effect include prolonged gastrointestinal transit time, reduced jejunal secretion and increased water and electrolyte absorption. In addition, as diarrhoea predominant IBS is associated with an exaggerated release of serotonin, reduction of serotonin release by octreotide may contribute as well.36

A possible explanation for the predominant negative findings in this study could be insufficient dosing. The choice of the current dose was based on the treatment schedule of patients with acromegaly, proven to suppress pituitary growth hormone secretion effectively.37 However, higher concentrations may be required to affect visceral sensation. Indeed, peak concentration after octreotide in the acute experiments is considerably higher than the steady-state concentration obtained with Sandostatin LAR. Half-an-hour after 100 μg of octreotide s.c., peak plasma concentration ranges between 2.8 and 5.2 ng/mL. In contrast, after 20 mg of intramuscularly injected of Sandostatin LAR, the steady-state concentration of octreotide varies between 1.2 and 2.5 ng/mL.38–40 Therefore, higher dosing may have revealed more pronounced effects than 20-mg octreotide used in the current study. Nevertheless, the fact that we did show an effect on first sensation and stool consistency suggests that the current dose was to some extent effective, albeit not optimal.

Secondly, differences in penetration of Sandostatin LAR, because of the relatively low dosage into the central nervous system, could be involved. This may be especially relevant assuming that the analgesic effect of octreotide is mediated by central mechanisms.41–43 In human, intrathecal octreotide results in a significant relief of pain caused by cancer.42, 43 In addition, Su et al. indeed showed a reduction in visceral nociception in rats after intrathecal administration of octreotide.44

Thirdly, chronic treatment with an octreotide analogue may lead to tachyphylaxis because of agonist-dependent receptor internalization and desensitization, a well-established phenomenon for STTR.34 SSTRs undergo internalization in a subtype-selective manner, with SSTR3 and SSTR5 far more prone to be rapidly internalized than SSTR2.37 SSTR2 is proven to be the most important receptor in the treatment of acromegaly, explaining the continued response to treatment in this disorder.45 However, we did not observe a reduction in the effect on stool consistency in time, making this explanation less likely.

Finally, it should be emphasized that this study is powered to detect a difference in the threshold of discomfort/pain during rectal distension. Therefore, the number of patients studied is too small to demonstrate an effect on symptom relief, implying that larger clinical trials with higher doses are required to further evaluate the effect of octreotide on global relief and gastrointestinal symptoms.

In conclusion, this study established the effect of prolonged treatment of non-constipated IBS patients with octreotide. Although the threshold of first rectal sensation increased and stool consistency improved, long-term treatment with octreotide, at least at the current dose used, has no visceral analgesic effect and fails to improve IBS symptoms.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Authors’ declaration of personal interests: None. Declaration of funding interests: The preparation of this paper was funded in part by Novartis Pharma B.V.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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