Gut 1994; supplement 3: S11 -S 14 Sll Octreotide in gastrointestinal motility disorders Gut: first published as 10.1136/gut.35.3_Suppl.S11 on 1 January 1994. Downloaded from C Owyang Abstract Intestinal effects of octreotide in The effects of octreotide on six normal scleroderma subjects and five patients with sclero- About 50% of patients with scleroderma have derma were investigated. Changes in small bowel dysfunction.5 In such patients, intestinal motility and in plasma motilin manometry shows patterns (known as the were examined after a single injection of migrating motor complex) in the small bowel octreotide. Octreotide stimulated intense during fasting6 and this may be clinically intestinal motor activity in normal sub- manifested as intestinal pseudo-obstruction jects. Motility patterns in the scleroderma and bacterial overgrowth. These problems are patients were chaotic and non-pro- difficult to treat because standard stimulatory pagative, but, after octreotide was given, prokinetic agents are not effective in sclero- became well coordinated, aborally derma.6 We therefore recently undertook a directed, and nearly as intense as in study to determine the effects of octreotide in normal volunteers. Clinical responses and six normal subjects and in five patients with changes in breath hydrogen were also scleroderma who had abdominal pain, nausea, evaluated in the five scleroderma patients bloating, and a change in intestinal contrac- who had further treatment with octreotide tility.7 We examined the changes in intestinal at a dose of 50 pugtday subcutaneously for motility and in plasma motilin, a gastrointesti- three weeks. A reduction in symptoms of nal hormone that stimulates intestinal motor abdominal pain, nausea, vomiting, and activity, after single injections of octreotide bloating was seen. Additionally, there was (10 ,ug subcutaneously for normal subjects an improvement in bacterial overgrowth and 100 pLg subcutaneously for scleroderma as objectively measured by breath hydro- patients). We also studied the clinical gen testing. The effects of octreotide (100 responses and changes in breath hydrogen pugtday subcutaneously) on the perception excretion (as a measure of intestinal bacterial of rectal distension were investigated in a overgrowth) in the five patients with sclero- double blind, placebo controlled study in derma who were additionally treated with healthy volunteers. Octreotide was shown octreotide for three weeks at a dose of 50 to reduce the perception of rectal disten- ,ug/day subcutaneously. The diagnosis of sion without affecting motor pathways or scleroderma was made according to the http://gut.bmj.com/ local rectal reflexes. This enhanced criteria developed by the Subcommittee of tolerance to volume distension seems to Scleroderma Criteria of the American result from inhibition of sensory afferent Rheumatism Association Diagnostic and pathways as shown by electroencephalo- Therapeutic Criteria Committee. graphic studies showing diminished evoked spinal and cortical potentials after octreotide. In irritable bowel syndrome SHORT TERM EFFECTS OF OCTREOTIDE ON on September 27, 2021 by guest. Protected copyright. patients with rectal urgency, octreotide INTESTINAL MOTILITY reduces rectal pressures and perception Normal subjects showed propagative intestinal after rectal distension to near normal patterns during fasting with mean (SD) 1-5 values. (1 0) phase III complexes occurring every three (Gut 1994; supplement 3: S 1 -S 14) hours (Fig 1). In contrast, none of the patients with scleroderma with pseudo-obstruction and bacterial overgrowth had any spontaneous Somatostatin has variable effects on motor duodenal phase III activity (Fig 1). Octreotide activity of the gastrointestinal tract depending induced propagative phase III activity on the physiological state and region of the originated in the duodenum in all the normal gastrointestinal tract studied. In the stomach, subjects, whereas gastric phase III activity was somatostatin inhibits the normal occurrence of suppressed. Duodenal phase III complexes Gastroenterology cyclic interdigestive and fed motor activities.1 evoked by octreotide were more frequent than Research Unit, In the intestine, somatostatin initiates ectopic spontaneous complexes. The normal subjects Departnent of Internal Medicine, The fronts under basal conditions2 but inhibits fed had 1-5 (1-0) phase III complexes during the University of Michigan motility. three hours of basal recording and 4 1 (1.1) Medical Center, Ann In normal subjects, somatostatin initiates a complexes during the three hours after Arbor, USA C Owyang propagative pattern of motor stimulants in the octreotide was given, or roughly one complex duodenum, with a shortened cycle length of every 40 minutes (p=0-012). The octreotide Correspondence to: motor consisted of Dr C Owyang, 40 minutes.3 The long acting somatostatin evoked patterns alternating Gastroenterology Research analogue, octreotide, used in the treatment phase I and phase III activity, with noticeable Unit, Department of Internal a in the duration of II Medicine, 3912 Taubman of endocrine tumours, evokes similar intesti- reduction phase activity. Medical Center, Box 0362, nal pattern of contraction in dogs.4 Therefore The responses to octreotide in the patients The University of Michigan were similar: octreotide Medical Center, Ann Arbor, octreotide may be potentially useful in the with scleroderma MI 48109, USA. treatment of small bowel dysmotility. increased the number of phase III complexes S12 Owyang from 0 to 3-6 (2 3) per three hours, which is similar to the responses seen in the normal [a Before octreotide | During octreotide| subjects. These complexes propagated at the 3-, same velocity and had two thirds the amplitude Gut: first published as 10.1136/gut.35.3_Suppl.S11 on 1 January 1994. Downloaded from of the spontaneous complexes in normal subjects. I In normal subjects, before octreotide, plasma motilin concentration mean (SD) was 92 (27) pmol/litre in phase I, rising to 112 0 pmollitre in phase III (p=0 05). The phase 0 cn I III complexes evoked by octreotide were E associated with a decrease in concentration to 0E 57 (16) pmol/itre (p=0006 compared with 0.C) phase I). Patients with scleroderma had cn persistently higher concentrations of plasma motilin (229 (74) pmol/litre, p=0-002 com- pared with phase I normal subjects before octreotide). As in normal subjects, this was decreased by octreotide to a value of 141 (76) pmolAlitre. These results suggest that the I * I Pain Nausea Bloating cycling of motilin is not necessary for Figure 2: Effect of three weeks of treatment with octreotide octreotide induced complexes. (50 ,g every evening) in patients with scleroderma. There is a significant decrease in the mean (SD) daily symptom scores for abdominal pain, nausea, and bloating during treatment with octreotide (p-0 05). Reproduced by the BREATH HYDROGEN EXCRETION AND kind permission of the N Engl J Med 1991; 325: 1461-7. GASTROINTESTINAL SYMPTOMS AFTER LONGTERM TREATMENT WITH OCTREOTIDE Breath hydrogen excretion was assessed in the hydrogen excretion after ingesting 50 g of patients with scleroderma before and after three glucose from 46 (24) to 8 (7) ppm (p=0-015). weeks of treatment with octreotide (50 ,ug After treatment none of the patients had subcutaneously at bedtime), to provide an increased breath hydrogen excretion while fast- objective measurement of the presence and ing, and only one of five had a breath hydrogen extent of bacterial overgrowth. Treatment with increase of more than 15 ppm at that time. octreotide reduced breath hydrogen excretion These results suggest substantial improvement while the patients were fasting from mean (SD) in intestinal bacterial overgrowth in all patients. 25 (5) to 4 (2) ppm (p=0 001) and breath Symptoms consistent with intestinal bacterial overgrowth and pseudo-obstruction were compared before and during the last http://gut.bmj.com/ Normal subject seven days of the three week period of treat- ment with octreotide. The mean (SD) daily symptom scores for abdominal pain decreased Basal from 2-0 (06) to 0-5 (0 5) during treatment 1 2 3 (p=0002). Similarly, the symptom scores for nausea decreased from 1-7 (1H1) to 0-2 (02) (p=005) and for bloating from 2-6 (0 6) to 0 5 on September 27, 2021 by guest. Protected copyright. (04) (p=0 003) (Fig 2). The number of episodes of emesis decreased from 3-7 (2 9) to 0 1 (O 2) per week (p=0 05). Finally there was After 10 of - fLI mIbhLIJh 3LLJ IJ I igg ILJLAI - octreotide 10111killow I.- ft no change in patients' weight before and during octreotide treatment. Patient with scleroderma SUMMARY Short term treatment with octreotide stimu- lated propagative intestinal phase III like activity in patients with pseudo-obstruction Basal secondary to scleroderma through motilin independent pathways. Treatment with octreotide for three weeks reversed abdominal breath hydrogen excretion and improved symptoms in patients with bacterial over- growth. These data suggest that octreotide After 100 jg of ..q1 may be useful for the treatment of intestinal octreotide dysmotility in patients with scleroderma. Figure 1: Intestinal manometric tracings in a normal subject and a patient with scleroderma. In the normal subject, the tracing shows a cyclic progression from the motor quiescence ofphase 1 through the irregular activity ofphase 2 to the intense phasic activity ofphase 3. Octreotide (10 ,ug) stimulated intestinal phase 3 activity that was qualitatively Antinociceptive