| Abstract|| |
Somatostatin is found in the pancreas and gastrointestinal tract, including the visceral autonomic nervous system, the endocrine D cells and the gut lumen. Somatostatin peptides may act differently at different sites as hormones, as paracrine substances or neurotransmitters. So far not much is known on the physiological effects of somatostatin in the gastrointestinal tract. Somatostatin and octreotide, a synthetic analogue with a longer half-life and higher potency, inhibit the neuroendocrine and exocrine gastrointestinal secretion, intestinal glucose, fat and amino acid transport, intestinal propulsive and gallbladder motility, splanchnic blood flow in volunteers and hepatic venous pressure in cirrhotic patients. The inhibition occurs to various extents depending on the target organ. This review deals with the pharmacological effects of octreotide on different gastrointestinal functions and describes the therapeutic role in different gastrointestinal disorders.
|How to cite this article:|
Meier RF, Reichert MM. Octreotide : A clinical update. Saudi J Gastroenterol 1998;4:147-55
In 1973 somatostatin-14, a cyclic tetradecapeptide was first isolated from ovine hypothalami when looking for growth hormone-releasing factors. The molecule found inhibited growth hormone release from pituitary cells. A second native form with 28 amino acids was found in 1980. This peptide acts as a precursor and also as a hormone in its own right, with a slightly different spectrum of activity in different tissues. Somatostatin is widely distributed throughout the gastrointestinal system, including the pancreas, visceral autonomic nervous system, endocrine D cells and the gut lumen,. Immunocytochemical and immuno-electron-microscopical studies demonstrated somatostatin in different cell types. They include classical open-type endocrine cells and paracrine cells with long cytoplasmic extensions. The paracrine cells occur mainly in the stomach and the pancreas. In the neurons of the intrinsic nervous system somatostatin exerts a neurotransmitter-like effect on adjacent cells.
Somatostatin-14 is the main molecular form in the duodenum, neurons and fibers of the submucosal and myenteric plexus and the pancreas The endocrine D cells of the body of the stomach, jejunum, ileum and colon contain somatostatin-28. In man the concentration of D cells decreases from the stomach to the lower colon. A very high concentration is found in the antrum. Recently, the knowledge on the physiological role of these peptides in man has increased, but still remains limited. Hildebrand et al. demonstrated that postprandial circulating levels of somatostatin-28, which is the main postprandial molecular form of somatostatin, is able to inhibit pancreatic enzyme secretion following stimulation by an intraduodenal amino acid mixture. Postprandial somatostatin-28 levels did not, however, have an effect on gastric acid secretion. These data indicate for the first time that postprandially circulating somatostatin-28 may well have a physiological role in modulating human exocrine pancreatic secretion. In contrast, a variety of pharmacological effects of somatostatin-14 on different gastrointestinal organ systems have been described.
After being released, somatostatin binds to specific receptors and achieves its effect by cyclic AMP-dependent and cyclic AMP-independent mechanisms,, Inhibition of adenylate cyclase is crucial to inhibit secretory processes. Somatostatin might further interact in the transcriptional process. The action of somatostatin-14 is short, nonselective and followed by a rebound secretion. The use of somatostatin-14 was limited by the necessity of continuous intravenous infusion due to its short half-life. Octreotide, an 8-amino acid synthetic analogue, lost some of the limitations of the native somatostatin . Octreotide is more selective, has a greater pharmacological activity and a longer half-life than the native molecule. The bioavailability after administration of octreotide is similar for intravenous infusion or subcutaneous injection. The different pharmacokinetic data of octreotide and somatostatin-14/28 are shown in, [Table - 1] ,,,
The administration of somatostatin- 14 and octreotide results in a potent inhibition of neuroendocrine and exocrine gastrointestinal secretion, intestinal transport, intestinal motility and splanchnic blood flow [Table - 2] . The extent of inhibition depends on the target organ. Beside these inhibitory effects, gastric mucous secretion, early gastric emptying and the intestinal migrating motor complexes, appear to be stimulated,,. Because of the different pharmacological effects octreotide is being used in the treatment of a variety of gastrointestinal disorders.
| Octreotide in esophageal varices and ulcer bleeding|| |
Bleeding of esophageal varices carries a high mortality risk of up to 60%; rebleeding occurs in up to 60% of patients, with a further 50% mortality for each rebleeding. Variceal bleeding stopped spontaneously in up to 60% of patients, Treatment is aimed at controlling acute bleeding and eliminating the risk of rebleeding [19,. Somatostatin and its analogue, octreotide, affect splanchnic hemodynamic parameters. Wahren and Eriksson reported decreases in total hepatic blood flow and hepatic vein wedge pressure in cirrhotic patients.
Baxter et al and Clement et a1, using direct varix puncture pressure measurements, noted a decrease in varix pressure following intravenous administration of octreotide in cirrhotic patients and also demonstrated a decrease in hepatic vein wedge pressure.
In 16 patients with recent variceal hemorrhage treated with octreotide, McKee found a 30% reduction in the portohepatic gradient, without significant change in pulse rate, arterial blood pressure or cardiac index.
In a controlled trial by McKee, 40 patients with active variceal bleeding were randomized to octreotide infusion (25 μg/h over 48 h) or esophageal tamponade. Control of bleeding over the first four hours was achieved in 19 of 20 episodes in the tamponade group and in 18 of 20 in the octreotide group. Complete control of bleeding over the 48-hour trial period was achieved in 14 patients of the tamponade group and in 10 patients of the octreotide group. Fifteen patients survived admission in the tamponade group compared with all the patients in the octreotide group. The two treatments gave comparable results in variceal bleeding. However, treatment was better tolerated in the octreotide group.
In a study by Sung et al, 100 patients were randomized to receive either emergency sclerotherapy or octreotide (50 μg intravenous bolus plus 50 μg/h intravenous infusion for 48 hours). At the end of the study period (48 hours), the octreotide group also had sclerotherapy to obliterate the varices. The Child-Pugh grading of the two groups were similar. Bleeding was initially controlled in 90% of patients by emergency sclerotherapy and in 84% by octreotide infusion. There were no significant differences between the two groups in early (within 48 hours of randomization) rebleeding (16 vs. 14%), blood transfusion (3 vs. 3.5 U), hospital stay (5 vs. 6 days) or hospital mortality (27 vs. 20%). No notable side effects were associated with octreotide. In this study octreotide infusion and emergency sclerotherapy were equally effective in controlling variceal hemorrhage.
In a multicenter randomized trial, Silvain et al compared the efficacy of terlipressin combined with transdermal nitroglycerin with that of octreotide in the emergency control of acute variceal hemorrhage in cirrhosis. Eighty-seven patients with endoscopically proven active bleeding from esophageal or cardiac varices were randomly assigned to receive intravenous terlipressin (2 mg and then I mg/4h over 24 hours) and transdermal nitroglycerin (10 mg/12h over 24 hours) or octreotide (continuous intravenous infusion of 25 µg/h over 12 hand subcutaneous injections of 100 μg at 12 and 18 hours). At 12 hours, bleeding was controlled in 59% (24 of 41) in the terlipressin/nitroglycerin group and in 78% (36/46) of the octreotide group (p = 0.064). The mean blood transfusion requirements were significantly increased in the terlipressin/nitroglycerin group compared to the octreotide group. After 12 hours, rebleeding occurred in 20% (5 of 24) in the terlipressin/nitroglycerin group and in 27% (10 of 36) in the octreotide group. After the 48-hour period, mortality was 12% (5 of 41) with terlipressin/nitroglycerin and 6% (3 of 46) with octreotide. In this study octreotide appeared to be as effective as terlipressin combined with transdermal nitroglycerin in the emergency control of active variceal bleeding in cirrhosis, with significantly smaller transfusion requirements and only minor side effects.
The double-blind prospective study by Besson et al in 199 patients with cirrhosis and acute variceal bleeding, showed a significant benefit when octreotide was given as an adjuvant treatment together with sclerotherapy. After five days, the proportion of patients who survived without rebleeding was higher in the sclerotherapy and octreotide group (87%) than in the sclerotherapy group alone (71%). The mean number of units of blood transfused within the first 24 hours after sclerotherapy was also lower in the octreotide group. It seems, that in patients with cirrhosis, the combination of sclerotherapy and octreotide is more effective than sclerotherapy alone. In the study of Jenkins et al 32 patients were treated by programmed injection sclerotherapy with or without subcutaneous octreotide 50 μg twice daily for six months. Significantly fewer patients receiving combined octreotide and sclerotherapy had episodes of recurrent variceal bleeding compared with patients given sclerotherapy alone (1/16 vs. 7/16; p < 0.037). Furthermore the survival was significantly improved. This improvement was maintained for 12 months after the end of the study period.
In an early double-blind placebo-controlled multicenter trial octreotide was not more effective in ulcer bleeding and preventing rebleeding compared to placebo. On the other hand a recently published study by Lin et al comparing intravenous octreotide (N 42) and ranitidine (N 42) in patients with active peptic ulcer bleeding or nonbleeding vessels found a hemostasis rate in 84% in the octreotide group compared to 55% in the ranitidine group (p < 0.01). Volume of blood transfused, numbers of patients receiving aggressive management (endoscopic hemostasis or operation) and hospital stay were significantly fewer in the octreotide group. No obvious side effects were found in the octreotide group.
| Octreotide in dumping syndrome|| |
Dumping syndrome is a rare but an important cause of morbidity after gastric surgery. Octreotide reduces symptoms of the early and late dumping syndrome. The therapeutic benefit is probably associated with a slower gastric emptying, small bowel transit time and inhibition of the peptide hormone release mediating vasomotor symptoms. In the main clinical studies of octreotide in dumping syndrome the patients received single dose of octreotide, 50 or 100μg s.c. 15-60 minutes before a test meal. Improvements were seen in the signs and symptoms of both early and late dumping. Changes caused by the test meal, e.g. in serum insulin, glucose, gastrointestinal peptides, pulse rate, systolic blood pressure and packed cell volume, were suppressed. The beneficial effects of subcutaneous octreotide in six patients with early dumping syndrome and six patients with late dumping syndrome have been described by Hopman et al In a placebo-controlled study patients with early dumping syndrome, 50 μg of octreotide abolished postprandial increases in pulse rate and improved symptoms. Increased plasma glucose and reduced plasma insulin responses to oral glucose were seen with the same dose in patients with late dumping syndrome. The abnormal breath hydrogen excretion normalized, indicating that gastrointestinal transit time is modified by octreotide.
In a placebo-controlled study of eight patients with dumping syndrome, Tulassay et al investigated the release of gastrointestinal hormones. The symptoms of early and late dumping were improved. The changes in packed cell volume, pulse rate and plasma VIP levels seen with early dumping were inhibited. The changes in plasma insulin and gastric inhibitory polypeptide seen with late dumping were suppressed.
Geer et al demonstrated in 10 patients that octreotide 100 μg suppressed the responses of gastrointestinal peptides to a test meal. Radiolabeling studies showed that octreotide prolonged gastric emptying. Long-term treatment led to stable fasting plasma glucose levels and to weight gain. Seven of the 10 patients who had been unable to work because of their symptoms were able to return to work.
Richards et al measured small-bowel motility in six patients with severe dumping syndrome in a randomized double-blind study. Octreotide 100 μg induced the occurrence of migrating myoelectric complexes characteristic of the fasting state and reduced the duration and vigor of postprandial motility.
Gray et al tested the effect of octreotide (100 μg s.c.) in a randomized, double-blind, crossover trial in nine patients with severe postprandial dumping symptoms after gastric surgery. Long-term studies have been conducted in another five patients Cetrotide remained equally effective over time.
| Octreotide in diarrhea|| |
In refractory diarrhea, octreotide is able to promote intestinal absorption of fluid and electrolytes and inhibit gastric, pancreatic and intestinal secretion. It may be acting via receptors that recognize VIP, since it is effective in controlling diarrhea associated with both VlPomas and AIDS. And there is evidence to suggest, that HIV may induce diarrhea by activating VIP-receptors,,,,,
Diabetes-associated diarrhea tends to be neuropathic rather than endocrine. In the rare case in which an APUDoma accounts for the coexistence of diabetes and diarrhea (glucagonoma, VIPoma), octreotide is the preferred treatment. However, octreotide has also been shown to be effective in patients with the commoner form of diabetes associated diarrhea. A dose-dependent decreases in stool weight and stool frequency and an improvement in orthostatic hypotension was seen
A number of studies have been published on the use of octreotide in AIDS-related diarrhea. Octreotide reduced both the frequency of bowel movements and the daily stool volume when administered in doses ranging from 50 μg twice daily to 500 μg three times daily. In a few patients who had concomitant cryptosporidia, cytomegalovirus colitis or microsporidiosis, treatment was less effective.
In a prospective, multicenter clinical trial of Cello et al, 51 patients infected with human immunodeficiency virus with uncontrolled diarrhea (> 500 ml liquid stool/day) were treated with octreotide 50 µg q.i.d. for 48 hours. If stool volume was not reduced to < 250 ml/day, the dose of octreotide was increased stepwise to 100, 250 and 500 μg. Twenty-one patients (41%) were considered to be partial of complete responders as shown by a reduction in daily stool volume by 50% or more of initial collection or a reduction to 250 ml/day or less. 0f the 21 responders, 14 (67%) had no identifiable pathogens at initial screening compared with nine of 30 (30%) non responders. The investigators concluded that patients with AIDS-associated refractory watery diarrhea, especially those without identifiable pathogens, may respond favorably to subcutaneously administered octreotide. The optimal therapeutic dose should be titrated on an individual patient basis.
| Octreotide in pancreatic surgery and in acute pancreatitis|| |
Major pancreatic resection is still accompanied by considerable morbidity (35%) and even mortality (10%),,,,. Typical complications such as pancreatic fistula and abscess are chiefly associated with exocrine pancreatic secretion. Therefore, the perioperative inhibition of exocrine pancreatic secretion is a promising concept in the prevention of complications. Two randomized, double-blind, placebo-controlled multicenter trials showed a reduction of postoperative complications when octreotide (3 times 100 μg for 7 days) was prophylactically given,. A significant reduction of complications such as fistula, abscess, fluid collection, sepsis and postoperative pancreatitis could be demonstrated in patients undergoing Whipple resection for cancer. The same effect was also demonstrated in patients with surgery in chronic pancreatitis
In acute pancreatitis, activation of digestive enzymes in the pancreas may play an important role. The release of toxic and vasoactive substances leads to life-threatening systemic, metabolic and organic complications,. The use of somatostatin or its analogue octreotide has been investigated in several clinical studies,,,. However, each study failed to prove a positive effect of somatostatin or octreotide treatment in acute pancreatitis mainly due to the low number of patients enrolled in the study protocols. A meta-analysis of six individual placebo-controlled studies in which somatostatin was given for acute pancreatitis showed that somatostatin significantly reduces mortality. A pilot trial in patients with moderate to severe acute pancreatitis showed a lower rate (although not statistically significant) of complications in patients treated with 3x200 or 3x500 μg/day octreotide compared with controls or patients receiving a lower dose of octreotide. A further study showed a significant reduction in patient-controlled analgesic consumption in patients treated with octreotide compared with controls
Up to now no conclusive evidence has been found for or against the use of somatostatin or octreotide in the treatment of acute pancreatitis. The results of a randomized, controlled multicenter study with an evaluable population of 300 patients, in Germany and Switzerland showed no clear benefit for octreotide (unpublished).
| Octreotide in gastrointestinal fistulas, ascites and pancreatic pseudocysts|| |
Some small studies showed a beneficial effect in patients with fistulas [Table - 3] ,,, pancreatic ascites,,,,, and pancreatic pseudocysts [Table - 4] ,, but these data are still controversial and must be further investigated by controlled trials.
| Octreotide and endocrine tumors|| |
Octreotide is particularly useful in patients with resistant acromegaly and some gastro-entero-pancreatic (GEP) tumors, e.g. VIPomas, carcinoids and glucagonomas. The efficacy of octreotide can be attributed to its actions regarding somatostatin receptors on GEP tumor cells. The symptoms of these tumors are due to a greater extent to peptides they secrete than to their actual size. In most patients symptoms improve or disappear completely with octreotide treatment.
The treatment of choice is surgical excision of the tumor. Frequently, surgery is not possible because of the presence of metastases or local invasion. The therapeutic possibilities in an inoperable GEP-tumor are very limited. Chemotherapy often has poor results and is associated with major adverse effects; symptomatic treatment, including steroids, lithium, indomethacin and ketanserin, has a low success rate. An alternative treatment in the future could be the use of octreotide and interferon,.
As even in inoperable metastatic tumors, the symptoms are mainly caused by the circulating tumor peptides, inhibition of the release of such peptides by octreotide can partly or even completely alleviate the symptoms in most patients. This can result in considerable improvement in the quality of life of such patients. One striking effect of octreotide treatment is the reduction of profuse secretory diarrhea induced by VIPomas,,. Dehydration and hypokalemia are reversed and the patients gain weight. The mean plasma VIP levels during the treatment decreased by about 60%.
Up to mid-1987, 82 patients in Europe had been treated with octreotide for endocrine GEP tumors. The drug was administered subcutaneously, in doses ranging from 50 μg/day to 200 gg three times daily. The results, in particular the response rates, are summarized in [Table - 5]. A definite improvement in the symptoms was rated as a response. Reductions in the tumor mass were seen in isolated cases of gastrinoma or VIPoma,. The success rate was particularly high in cases of VIPoma and slightly lower in cases of carcinoids. Kvols from the Mayo Clinic reported on 66 patients with carcinoid syndrome (refractory to other forms of treatments) a complete or near-complete control of symptoms with octreotide. Diarrhea decreased in 77% and flushing in 87% of the patients. Over 50% of the patients with gastrinoma were treated with octreotide (100-1,500 μg/day). In 90% gastric hypersecretion, pain and diarrhea could be controlled. Since the proton pump blocker are so effective in suppressing acid secretion, octreotide is less used in the treatment of Zollinger-Ellison syndrome.
The response rate of octreotide in insulinomas and glucagonomas was less than for carcinoids and VIPomas, although the migratory, necrolytic dermatitis resolved in 90% of glucagonoma patients. Octreotide is currently the drug of choice for controlling the symptoms of inoperable GEP tumors. For these tumors the newly developed long acting octreotide will have a great impact in the treatment of these tumors, due to fewer injections.
| Adverse effects|| |
Treatment with octreotide was associated with adverse effects in about 50% of the patients. These consisted mainly of pain at the subcutaneous injection site or gastrointestinal symptoms such as nausea, vomiting, retrosternal discomfort, flatulence, diarrhea, or steatorrhea. None of the side effects necessitated a withdrawal of the treatment. It should also be borne in mind that the administration of octreotide is often necessary at high doses and for long periods of time. Steatorrhea is well controlled with oral pancreatic enzyme replacement. Fecal fat measurement is a good guide for the replacement therapy. Gallbladder contraction is also inhibited by octreotide treatment. This inhibition of gallbladder contraction may lead to gallstone formation during long-term therapy. Preliminary results suggest that there is a linear relationship between the duration of octreotide treatment and the incidence of gallstones. Most of these gallstones were asymptomatic and only few patients had to be operated on. This complication should be prevented by periodic ultrasound imaging. In rare cases an escape and rebound phenomenon reported by Koelz et al can occur. This was described in two patients with VIPomas. During treatment with octreotide, diarrhea occurred again more frequently with a concurrent rise in the plasma VIP levels. By changing the dose regimen to intermittent administration, it was possible to restore full efficacy in one case.
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Remy F Meier
Department of Gastroenterology, University Hospital, CH-4410, Liestal,
Source of Support: None, Conflict of Interest: None
[Table - 1], [Table - 2], [Table - 3], [Table - 4], [Table - 5]