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Abstract

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

Background:

Somatostatin and octreotide have multiple effects which make them ideal for treating diarrhoea of different aetiologies. Their use in a variety of conditions with refractory diarrhoea, however, is based on a limited number of studies.

Aim:

We undertook a systematic review of the available English literature to maximize an evidence-based approach to the treatment of refractory diarrhoea. We tested the hypothesis that efficacy is independent of aetiology.

Methods and results

A Medline and individual article search from 1965 to 2000 was undertaken on the use of somatostatin and octreotide in diarrrhoea. All reports containing at least five subjects were included. The percentage response in case series and randomized controlled trials was compared, and a meta-analysis of randomized controlled trials where patient level data were provided was carried out. There were 30 publications found (18 case series, 12 randomized controlled trials). The response percentage was 73% overall in case series and 64% in randomized controlled trials (not significant). A meta-analysis of nine randomized controlled trials revealed significant heterogeneity despite an overall relative risk of 0.5 (95% confidence interval, 0.27–0.91). Subgroup analysis of the largest aetiological groups showed that acquired immunodeficiency syndrome studies were homogeneous, but somatostatin and octreotide were less effective. Post-chemotherapy studies remained heterogeneous and somatostatin and octreotide were highly effective.

Conclusions

While this review strengthens the consensus guidelines on the use of somatostatin and octreotide for refractory diarrhoea, evidence-based support requires additional studies.


INTRODUCTION

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

During the last three decades, somatostatin has been implicated as a mediator to decrease diarrhoea, because it decreases gastrointestinal motility and intestinal fluid and electrolyte transport. It was initially discovered in 1968 by accident during studies looking for a growth hormone releasing factor in the rat pituitary,1 and was subsequently isolated.2 Because of its short half-life and tachyphylaxis, biochemical manipulation of somatostatin was attempted to produce products with a longer half-life and improved pharmacological properties.3 The best known and most widely used of these is octreotide.

Both somatostatin and octreotide exert their biological effects by interacting with five subtypes of receptors (SRs), each produced as a product from different chromosomes.4 While somatostatin is non-selective, octreotide interacts mainly with SR2 and SR5 and less so with SR3. The interaction of somatostatin or octreotide results in the inactivation of adenylate cyclase or the inhibition of Ca2+ influx and K+ efflux via G-inhibiting proteins and, consequently, should be effective in a variety of cases of water malabsorption and diarrhoea. These functions, coupled with a good safety profile, have been useful in the treatment of a number of clinically important gastrointestinal diseases.5 Although octreotide is approved and used for symptoms resulting from carcinoid and vasointestinal pancreatic hormone producing tumours, it is still not completely accepted for use in a number of other conditions associated with refractory diarrhoea.

Refractory diarrhoea has been defined in previous reviews as: ‘diarrhoea of more than 14 days’ duration that does not respond to either specific therapy or to usual anti-diarrhoea preparations’.6, 7 Under this rubric, Farthing lists some 30 conditions.7 However, there are relatively few controlled trials on individual causes of refractory diarrhoea, making evidence-based judgement on the efficacy of somatostatin or octreotide in these conditions difficult. To the practising gastroenterologist, the most common clinical problems associated with refractory diarrhoea include acquired immunodeficiency syndrome (AIDS), post-chemotherapy, graft vs. host disease, post-gastrectomy dumping syndrome, short gut high ileostomy output and some infectious diarrhoeas (e.g. cholera). Because somatostatin/octreotide affect common mediators of diarrhoea at the cellular level, we hypothesize that they can improve patients’ diarrhoea independent of the different aetiologies listed. Therefore, the objective of the current study was to update the literature on available case series pertaining to refractory diarrhoea, and to conduct a meta-analysis of available randomized controlled trials on the subject. Diarrhoea associated with endocrine tumours (apudomas) will not be discussed, as octreotide is already used routinely in some of these tumours (carcinoid vipoma).8

METHODS

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

We reviewed the English language literature by searching the Medline (1968–2000) and Cochrane (1996–2000) library using the MeSH words (diarrhoea) AND (somatostatin OR octreotide) AND (AIDS OR post-chemotherapy OR cisplatin OR 5-fluorouracil). We also perused review articles of somatostatin/octreotide use with refractory diarrhoea, the pharmacology of octreotide and somatostatin and individual references. The titles of the references from these articles were also reviewed for any articles that may have been missed from the search strategy. Although case reports may be quoted, case series with five or more patients are tabulated. Controlled studies were accepted if the publication provided specification of the subjects’ responses compared with those in a control group.

Eligible randomized controlled trials were subsequently analysed for heterogeneity, and relative risks (random effects model) were calculated using Reviewer Manager version 4.1 Cochrane collaboration. The number of patients needed to be treated (NNT) was calculated using the formula 1/ARR, where ARR=absolute risk reduction.

Although there were several randomized controlled trials, there were also a large number of patients from case series and we did not feel it appropriate to ignore these data a priori. Examining the similarities and differences in the results between studies can provide insight that might otherwise be lost.9, 10 To determine if the responses of patients treated in case series were different from those of patients treated in randomized controlled trials, we compared the overall percentage of patients who responded to treatment in randomized controlled trials with those who responded to treatment in case series. The results are expressed as the percentage ± s.e. using combined individual data, and as the mean percentage ± s.e. using group-level data, i.e. the percentage of people who responded within each study was used as a continuous variable. We recognize the limitations of this approach and present the results only as a rough estimate and as hypothesis generating.

RESULTS

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

The results of our search disclosed a total of 30 publications containing at least five patients each.11–42 Of these, 18 were case series with a total of 324 patients.11–28 There were eight randomized controlled trials with a total of 354 patients (195 treated and 159 controls),30–37 and four randomized controlled crossover design studies with an additional total of 34 patients,29, 38–40 i.e. a total of 12 randomized controlled trials with 229 treated patients and 193 controls. All 30 of the studies were full publications.

Table 1 lists the features of the case series. The dose and route of somatostatin or octreotide used in the various studies are also listed. Octreotide was used in all case series; an escalating dose from 50 μcg subcutaneously to as high as 5000 μcg subcutaneously every 8 h was used in 15 studies, while three studies used the intravenous route only. The duration also varied from as little as 48 h to 33 weeks. In nine case series, the definition of response based on either stool volume or frequency was considered to be complete if there was an absence of diarrhoea after therapy, or partial if there was a 50% reduction in diarrhoea after therapy. In seven case series, various ranges of reduction of diarrhoea were considered as a response. In two studies, mean decreases in stool volume or stool weight are reported.

Table 1.   Uncontrolled prospective studies on the use of octreotide (O) or somatostatin (S) for refractory diarrhoea Thumbnail image of

Table 2 lists the features of the randomized controlled trials. Five of the 12 randomized controlled trials were double-blind,31, 34, 38–40 two were single-blind30, 32 and five were unblind.29, 32, 35–37 A true placebo (saline) alone was used in the control group in five studies34, 37, 38 and, in one of these five studies, octreotide was given prophylactically rather than as treatment.34 In the remaining studies, octreotide was compared with existing anti-diarrhoeal agents, such as loperamide or acetorphan, and in one study on cholera antibiotics were used with placebo injections.36 There was similar variability in dose ranges among the randomized controlled trials, and three of the studies used intravenous somatostatin. The duration of therapy was shorter than in the case series, ranging from 12 h to 2 weeks. In randomized controlled trials, the definition of response was reported in different ways. While two studies used a 50% reduction of diarrhoea as defining a response,30, 35 Simon et al. used a 30% reduction from baseline31 as a positive response. Five of the studies used descriptive terms, such as absence or loss of diarrhoea.29, 32–34, 38 The remaining four studies measured mean stool volume,36, 37 ileostomy output40 or net fluid absorption.39

Table 2.   Controlled prospective trials of either octreotide (O) or somatostatin (S) for refractory diarrhoea Thumbnail image of

The main aetiological causes of refractory diarrhoea in the studies were AIDS, post-chemotherapy, graft vs. host disease, cholera, post-gastrectomy, short bowel syndrome and ileostomy output. Post-chemotherapy and AIDS were the largest groups in both case series and randomized controlled trials.

The percentage of patients who responded to somatostatin/octreotide for the different aetiologies of refractory diarrhoea showed a wide distribution in both case series and randomized controlled trials (Figure 1). Without implying validity to combine studies, a rough estimate of mean response to somatostatin/octreotide based on individual patient data was 74 ± 3% in case series and 64 ± 3% in randomized controlled trials. A rough estimate of mean response to somatostatin/octreotide based on group-level data was 71 ± 1% in case series and 68 ± 3% in randomized controlled trials. These results were not significantly different.

image

Figure 1.  Percentage of patients who responded to somatostatin or octreotide within each study, grouped by study design (case series vs. ‘cases’ within randomized controlled trials, RCTs). Each symbol represents a different condition, as noted in the figure. The thick horizontal lines represent the mean of all studies, i.e. grouped patient data mean and not the mean of individual patients. Two studies reported decreases in stool volume or weight in 100% of patients, but the degree varied and the authors did not state a priori cut-offs for ‘responder’. These two studies are not indicated in the figure but are present in Table 1. AIDS, acquired immunodeficiency syndrome; post-chemo, post-chemotherapy of any type; GVHD, graft vs. host disease.

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For the case series, 35% of patients had a complete response, 29% had a partial response and 36% had no response. There was marked heterogeneity of responses between different categories. For example, two of the case series on AIDS found that patients without identifiable pathogens responded better than those with cryptosporidia.14, 15 For patients with graft vs. host disease, 86.3% responded to somatostatin/octreotide,23–25 whereas only 37.5% of patients with dumping-related diarrhoea responded to these drugs.26

In nine of the 12 randomized controlled trials, enough patient level data were given29–35, 38 or were deducible36 to attempt to formulate a meta-analysis (Figure 2). Of these nine studies, there were 206 treated patients and 172 controls. In the treated group, 131 patients (64%) had a partial or complete response and, in the control group, 59 patients (34%). However, the test of heterogeneity of these studies is highly significant (P < 0.001) suggesting marked variability among the trials. As a hypothesis-generating exercise, we still calculated a relative risk of 0.49 (95% CI: 0.27, 0.90), an ARR of 0.34 (95% CI: 0.59, 0.08) and an NNT of 2.9 (95% CI: 1.7, 12.5). Subgroup analysis of response rates within aetiological divisions shows that the AIDS studies are homogeneous (P ≤ 0.25), while post-chemotherapy remains highly heterogeneous (P < 0.001). However, the relative risk in the AIDS studies alone suggests less of an effect with a value of 0.86 (95% CI: 0.62, 1.19) and an NNT of 8.3 (95% CI: 3.0, 11.1).

image

Figure 2.  Relative risks (± 95% CI) for all randomized controlled trials calculated on the basis of the random effects model. Studies are grouped according to disease categories. Values less than 1 mean that somatostatin/octreotide were more effective in treating diarrhoea compared to control, and values greater than 1 mean that somatstatin/octreotide were less effective than control. The identity of the substance used as control is also provided. Note that somatostatin/octreotide appear to be more effective when compared against placebo than when compared against loperamide, although the confidence intervals are large.

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The remaining three trials37, 39, 40 could not be included due to a lack of availability of patient level data. However, in the two crossover studies, all 11 patients did better with therapy compared to control conditions.39, 40 In the study by Molla et al., there was no difference between somatostatin-treated and placebo-treated patients.37

With regard to the quantitative comparison of outcome in each aetiological category, we felt that the small numbers of cases in each category precluded a valid statistical analysis. However, a qualitative assessment of outcomes in both case series and randomized controlled trials suggests rejection of our contention that the physiological effects of somatostatin/octreotide should exert similar benefits in each category.

DISCUSSION

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

The anti-diarrhoeal effects of somatostatin are multifactorial. The inhibition of the effects of many gastrointestinal hormones, such as gastrin, vasoactive intestinal peptide, pancreatic polypeptide and serotonin, led to its use in carcinoid tumour41–43 and pancreatic cholera syndrome.44 In a series of in vivo and in vitro studies, it was systematically shown that somatostatin could block the secretion of electrolytes. Both cyclic adenosine monophosphate-mediated transport as well as processes beyond cyclic adenosine monophosphate formation were inhibited in the rat colon and jejunum.45, 46 Furthermore, both Na+ and Cl absorption were increased in the rabbit ileum.47, 48 It was also subsequently demonstrated that prolongation of intestinal transit could significantly contribute to reduction in diarrhoea even when no secretagogue was present.49 Most recently, in vitro octreotide was shown to inhibit secretion induced by fraction 5 of the gp-41 protein of human immunodeficiency virus.50 This latter finding may partly explain the better outcome in AIDS patients without identified pathogens reported in some,14, 15 but not other,31 publications.

Initial reports of improvement in AIDS diarrhoea, short gut syndrome and diarrhoea caused by diabetic autonomic neuropathy appeared in the 1980s.51–54 Subsequently, larger trials in the areas reported herein followed. Although there have been a number of reviews on the use of octreotide in refractory diarrhoea, a systematic evaluation has not been carried out. As octreotide has such a wide array of effects that may be beneficial for the therapy of diarrhoea, we tested the hypothesis that the hormone and its analogue are useful for diarrhoea of multiple causes independent of aetiology.

In order to evaluate the hypothesis, we surveyed all studies in which at least five subjects were reported. Although a total of 30 studies overall was found, only the study by Simon et al.31 included more than 100 patients. The dosing schedules varied from study to study; however, they were fairly uniform in the two largest disease categories of AIDS and post-chemotherapy. The duration of dosing was longest in the AIDS trials, and in the single study by Mackie et al.26 the variation was from days to weeks. Although tachyphylaxis has been reported with octreotide in some conditions,55, 56 it was not considered to occur over the time intervals in the studies reviewed here.

The controlled trials also differed markedly from one another. The duration of studies varied from 12 h to 3 weeks, with a median of 2 days. However, because a response was noted with short duration studies, the length of time octreotide/somatostatin was given is not likely to account for the variability in outcome observed across the studies. One-third of the studies used intravenous somatostatin or octreotide, and the rest used a somewhat narrower range of subcutaneous dosages of octreotide. Of the 12 randomized controlled trials, four used a crossover design, five used a true placebo,34, 37–40 six used anti-diarrhoeal agents29–33, 35 and one used antibiotics36 in the control group. The use of anti-diarrhoeal agents may be expected to reduce statistically the true effects of somatostatin/octreotide. In addition, the different anti-diarrhoeal agents used also exhibit different levels of efficacy, which may contribute to the variability across studies.

Although the combination of patients in the case series group is not meant to be statistically reliable, a crude comparison showed that the percentage of AIDS patients who responded to octreotide/somatostatin was less than the percentage of chemotherapy patients who responded. This reduced response is also reflected by the AIDS subgroup meta-analysis, where a modest but insignificant benefit of octreotide is shown. Interestingly, a more distinct benefit of octreotide was reported in the uncontrolled phase of the study by Simon et al.31 The dose of octreotide was much higher in this phase of the study. Therefore, it is possible that the use of larger initial doses of octreotide is needed in AIDS patients to show increased benefit over standard anti-diarrhoeal agents. More research is needed to confirm or refute this hypothesis.

Both case series and randomized controlled trials appear to show distinctly desirable benefits of octreotide in post-chemotherapy refractory diarrhoea. Unfortunately, the four randomized controlled trials differed significantly from each other, suggesting that combining them for statistical analysis may not be valid. These trials differed in terms of the doses used, routes and duration of administration of octreotide. Moreover, the study by Cascinu et al.34 used low-dose octreotide for prophylaxis in patients in whom diarrhoea occurred historically prior to the next cycle of chemotherapy. Finally, in the study of Geller et al.,35 intravenous doses of octreotide in some patients were given via total parenteral nutrition lines, raising the possibility of decreased octreotide bioavailability due to binding to amino acids. It is not possible to distinguish the percentage of patients who responded to any particular chemotherapeutic agent as a number of different drugs were used in the various studies.

Although the case series report a high percentage of patients with graft vs. host disease who responded, there are no controlled trials to confirm this observation.

Studies on post-gastrectomy dumping-related diarrhoea, short gut syndrome and ileostomy output were reported only in small numbers, but somatostatin/octreotide show promising results. In addition, they have the advantage of using a crossover design in each trial. However, confirmation with larger studies would strengthen their conclusion, as a recent report of the effect of long-acting octreotide failed to show clinical benefit in short gut syndrome.57 Overall, the variability in response rates in individual aetiological categories qualitatively suggests that somatostatin/octreotide do not equally benefit all types of diarrhoea. Because to date the putative mechanisms of the anti-diarrhoeal effect have been assumed to be similar for somatostatin and octreotide, the implication is that the different listed aetiologies have different mechanisms of diarrhoea.

In conclusion, this systematic review lends support to the beneficial effect of somatostatin/octreotide as therapy for refractory diarrhoea. However, the conclusion is based on limited numbers of patients and therefore the magnitude of benefit remains in question. Furthermore, our original hypothesis that somatostatin/octreotide are equally beneficial in diarrhoea of any aetiology needs to be further assessed. There are few controlled trials and those that do exist vary greatly from each other in the type of patients, indication for therapy (active or prophylactic), dosages, routes and length of time of administration of somatostatin/octreotide. In the available controlled trials, the demonstration of a similar benefit (at least statistically) is biased against somatostatin/octreotide because different anti-diarrhoeal agents with varying effectiveness were used instead of true placebo. However, ethical considerations may mitigate against the use of placebo only in subsequent trials. Nevertheless, the favourable responses reported in most of the reviewed studies cannot be ignored and, as such, the current review supports and strengthens consensus guidelines on the use of somatostatin/octreotide in refractory diarrhoea.58 Proof of efficacy, however, will require larger prospective clinical trials that take into consideration the criticisms outlined in this study.

References

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