Editorials

Somatostatin in gastroenterology

Octreotide is useful in the management of unresectable hormone secreting neuroendocrine tumours, particularly carcinoids and vipomas.² It inhibits both the secretion and the effect of the active agent. For example, in vipomas characterised by profuse secretory diarrhoea, octreotide reduces the diarrhoea by inhibiting the secretion of vasoactive intestinal polypeptide and by directly reducing intestinal secretion. Responsiveness often falls - perhaps because of down regulation of somatostatin receptors on tumour cells or the emergence of a receptor negative clone. The absence of a consistent antiproliferative effect may be related to the poor affinity of octreotide for some of the somatostatin receptor subtypes found on these tumours. Nevertheless, the high density of somatostatin receptors on most gastrointestinal neuroendocrine tumours has allowed tumours to be localised with in vivo scintigraphy with labelled octreotide.³

In clinical practice these peptides have probably had their greatest impact in the management of bleeding varices, gastrointestinal fistulas, and complications of pancreatic surgery. Somatostatin reduces splanchnic arterial blood flow, portal flow, and gastric mucosal blood flow. In addition, it inhibits the secretion of gastric acid and pepsinogen and stimulates the secretion of gastric mucus. For these reasons the efficacy of these agents on upper gastrointestinal haemorrhage has received considerable attention. The effectiveness of somatostatin or octreotide in variceal bleeding has been tested in over a dozen published controlled trials. In the largest (120 patients) and most carefully designed study, somatostatin 250 µg per hour (equivalent to octreotide 25 µg per hour) for five days was better than placebo in controlling bleeding and reducing transfusion requirement. ⁴ Other studies have shown that somatostatin or octreotide is as effective as vasopressin infusion, balloon tamponade, or emergency sclerotherapy.^5,6No study has shown a beneficial effect on mortality. Importantly, somatostatin and octreotide have fewer cardiovascular side effects than vasopressin and are cheaper on a cost per hour basis at least in Australia. In contrast (and somewhat surprisingly), somatostatin and octreotide provide no benefit in bleeding from peptic ulcer.⁷

Because of their inhibitory effects on pancreatic secretion the peptides have been suggested as treatment for pancreatic fistulas, pancreatic ascites, and possibly also pseudocysts, but there have been no controlled trials.⁸ Disappointingly, four controlled trials (in a total of 375 patients) have failed to show benefit in acute pancreatitis.⁹ Furthermore, a recent large randomised controlled trial failed to show any benefit of octreotide on the pain and pancreatitis after endoscopic retrograde cholangiopancreatography. In fact, failure of sphincteric cannulation was more common in the treatment group, and the authors suggested that any potential benefit of octreotide in suppressing pancreatic secretion may be offset by its effect on the sphincter of Oddi, where it increases basal tone and the frequency of phasic contractions.*RF 10 More encouraging are the data from two large multicentre European trials suggesting that perioperative and postoperative octreotide reduces the rate of local complications after major pancreatic surgery.^11,12

Because of their inhibitory effects on intestinal secretion the agents have been used in cases of enterocutaneous fistulas. One controlled trial compared total parenteral nutrition and octreotide with total parenteral nutrition alone. Both regimens were similarly effective, but fistulas closed faster with octreotide.¹³

As surgery for peptic ulcer disease becomes rarer so too does the dumping syndrome. Most patients with this syndrome can be adequately managed by dietary means, but there exists a small subset of patients severely disabled by their symptoms. Several placebo based trials have shown that somatostatin or octreotide given before eating benefits both early and late dumping.¹⁴ Somatostatin and octreotide reportedly improve secretory diarrhoeas other than those associated with neuroendocrine tumours. Control of secretory diarrhoea associated with the short bowel syndrome, ileostomy diarrhoea, idiopathic secretory diarrhoea, diarrhoea associated with amyloidosis, and diabetic diarrhoea has been reported, but no controlled trials have been performed.¹⁵ The agents have no effect on the diarrhoea of cholera. Octreotide has shown some promise in the management of refractory diarrhoea related to AIDS, especially in patients without identifiable pathogens.¹⁶ After years of mostly uncontrolled studies, a series of randomised controlled trials is defining the clinical applications of octreotide.¹⁷ Nevertheless, analogues of somatostatin with special affinities for the different classes of somatostatin receptors are needed. Now that the sequences of many of the somatostatin receptor subtypes are being described,¹⁸ the synthesis of analogues targeted for specific clinical applications should be possible.

A Shulkes, J S Wilson 

1. Nielson-Piercy C, Hammond PJ, Gwiliam ME, Khandan-Nia N, Myers MJ, Gahtei MA, et al. Effect of a new oral somatostatin analog (SOZ COGH) on gastric emptying mouth to cecum transit time and pancreatic and gut hormone release in normal male subjects. J Clin Endocrinol Metab 1994;78:329-36. [Abstract]
2. Gordon P, Comi P, Maton PN, Go VLW. Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract. Ann Intern Med 1989;110:35-50.
3. Lamberts SW, Ghagviale JA, Krenning EP. The visualisation of gastroenteropancreatic tumors. Digestion 1993;54(sppl 1): 92-7.
4. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D'hyeygere F, McIntyre N. Randomised double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Gastroenterology 1990;99:1388-95. [Medline]
5. Jaramillo FL, de la Mata M, Costan MO, Gomez - Camacho F. Somatostatin versus Sengstaken balloon tamponade for primary haemostasia of bleeding oesophegeal varices. J Hepatol 1991;12:100-5. [Medline]
6. Sung JJ, Chung SC, Lai CW, Chan FK, Leung JW, Yung MY, et al. Octreotide infusion or emergency sclerotherapy for variceal haemorrhage. Lancet 1993;342:637-41. [Medline]
7. Christiansen J, Ottonjann R, Von Arx F, and the Study Group. Placebo - controlled trial with the somatostatin analogue SMS 201-995 in peptic ulcer bleeding. Gastroenterology 1989;97:568-74. [Medline]
8. Layer P, Ohe MVD, Muller MK, Beglinger C. Effects of somatostatin on the exocrine pancreas. Scand J Gastroenterol 1991;26:129-36. [Medline]
9. McKay CJ, Imrie CW, Baxter JN. Somatostatin and somatostatin analogues - are they indicated in the management of acute pancreatitis? Gut 1993;34:1622-6.
10. Binmoeller KF, Harris AG, Dumas R, Grimaldi C, Delmont JP. Does the somatostatin analogue octreotide protect against ERCP incduced pancreatitis? Gut 1992;33:1129-33.
11. Buchler M, Friess H, Klempa I. Role of octreotide in the prevention of postoperative complications following pancreatic resection. Am J Surg 1992;163:125-31. [Medline]
12. Bassi C, Falconi M, Lombardi D, Briani G, Vesentini S, Camboni MG, et al. Prophylaxis of complications after pancreatic surgery; results of a multicenter trial in Italy. Digestion 1994;55(suppl 1):41-7.
13. Torres A, Landa JI, Moreno - Azcoita M, Arguello JM, Silecchia G, Castro J, et al. Somatostatin in the management of gastrointestinal fistulas. Arch Surg 1992;127:97-100. [Abstract]
14. Gray JL, Debas HT, Mulvihill SJ. Control of dumping symptoms by somatostatin analogue in patients after gastric surgery. Arch Surg 1991;126:1231-6. [Abstract]
15. Nightingale JMD, Lennard Jones JE, Walker ER, Farthing MJG. Jejunal efflux in short bowel syndrome. Lancet 1990;336:765-8. [Medline]
16. Cello JP, Grendell JH, Basuk P, Simon D, Wittner M, Rood RP, et al. Effect of octreotide on refractory AIDS - associated diarrhea. A prospective multicenter clinical trial. Ann Intern Med 1991;115:705-9.
17. Shulkes A. Somatostatin: physiology and clinical applications. Baillieres Clin Endocrinol Metab 1994;8:215-36. 18. Bell GI, Reisihe T. Molecular biology of somatostatin receptors. Trends in Neurosciences 1993;16:34-8. [Medline]