Aliment. Pharmacol. Ther. (1992) 6 , 685-691.
Effect of sumatriptan, a new selective 5HT,-like agonist, on liquid gastric emptying in man
L. A. H O U G H T O N " , P. FOWLERt, 0.N. KEENEt & N. W. READ* * Sub-Department of Gastrointestinal Physiology and Nutrition, University of Shefield, Shefield, and t Glaxo Group Research Ltd, Park Road, Ware, Hertfordshire, U K Accepted for publication 13 July 1992
SUMMARY
Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT,-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine. INTRODUCTION Sumatriptan is a new selective 5-HT1-like agonist which has been shown to be effective in the treatment of migraine. Its mechanism of action in man is unknown, but studies carried out in both cats and dogs suggest that sumatriptan might be acting by selectively constricting the arteriovenous anastomoses." Correspondence to: Dr L. A. Houghton, Department of Medicine, University Hospital of South Manchester, Nell Lane, Didsbury, Manchester M20 8LR, UK. 685
686
L.A. H O U G H T O N
ef al.
Administration of sumatriptan (0.3-1.0 mg/kg p.0.) accelerates gastric emptying in the rat3 and since migraine is associated with nausea, vomiting and slow gastric emptying, the purpose of this study was to test whether sumatriptan might help to relieve symptoms of nausea and vomiting during migraine attacks by accelerating gastric emptying in humans. Paired gamma camera studies were therefore carried out in 12 healthy male subjects to investigate the effect of sumatriptan and metoclopramide (a positive control) on the rate of gastric emptying of a fatty liquid-test meal. MATERIALS A N D M E T H O D S Subjects Studies were carried out on 12 healthy male subjects, aged between 20 and 39 years. Each subject underwent a full medical examination and laboratory investigations of blood and urine before entering the study, and in each case the results of these investigations were normal. All subjects gave their fully informed consent for the study to be carried out. The equipment conformed to the safety standards laid down by the Department of Health and the study was carried out in accordance with the Declaration of Helsinki and with approval of the Ethics Sub-committee of the Shefield Southern District Hospitals. Experimental protocol The subjects were studied on three separate occasions separated by periods of at least 1 week. O n each occasion, they were given either intravenous 3 mg sumatriptan (Glaxo, Ware, Herts, UK), 10 mg metoclopramide (Beechams, Harlow, Essex, UK), or saline control. The order of administration of the drugs and saline control was randomized and double-blind. Subjects fasted for at least 12 h before each study. No alcohol was permitted for 24 h before each study and cigarette smoking was not allowed on the study day. O n the day of the study a cannula was inserted into a suitable forearm vein for infusion of the drug or placebo. The subject then sat vertically against a posteriorly positioned gamma camera (Model 1201 Pho/Gamma Scintillation Camera, Nuclear-Chicago, Europa NV, Amsterdam, The Netherlands) and one of the treatments infused intravenously over 10 min at a rate of 1ml/min. At the end of the i.v. infusion the indwelling cannula was removed and the subjects drank 300 ml of warmed (approx 40 "C) soup (Beef Consommg, Campbell Grocery Products, Kings Lynn, Norfolk containing 3 g fat, 1.2 g carbohydrate, 1.8 g protein) to which had been added 30 g (228 kcal) margarine (Suma Sunflower Margarine, Halifax, West Yorkshire)and 1.89 MBq 99mTechnetium tin colloid. The margarine was mixed into the soup using a blender and studies in vitvo have shown that the fat does not separate out after a period of 3 h, even when 0.1 M hydrochloric acid was added.
SUMATRIPTAN A N D L I Q U I D GASTRIC EMPTYING
687
This soup has been used before in previous studies4 and is considered appetizing. All subjects consumed the soup within one minute.
Measurement of gasfric emptying Images of the distribution of the radioactivity in the abdominal cavity were collected over consecutive 2-min periods for the first 45 frames and then over consecutive 5-min periods for a further 1 2 frames. The total period of data collection was 150 min. Data collection began at the start of liquid ingestion. At the end of the study, a further 1.89 MBq 99"Technetium-tin colloid in 150 ml water was given orally and a left lateral image of the stomach was acquired over 5 min so that the images of the stomach, obtained by the posteriorly positioned gamma camera could be corrected for tissue attenuation caused by the isotope moving away from the gamma camera as the meal e m ~ t i e d , ~ , ~ To analyse the gamma camera records, the position of the stomach was identified from the images obtained during the first 10 min of the study and outlined using a cursor. Sub-areas were also defined to enclose the proximal (fundus and . ~ computer then body of stomach) and distal (antrum) regions of the ~ t o m a c hThe extracted the counts from each region of interest, corrected them for decay and tissue attenuation and expressed them as a percentage of the counts obtained in the gastric region immediately after ingestion of the meal. These figures were then used to construct profiles of the proportion of counts in the whole stomach and in each sub-region throughout the study. The profiles of whole stomach emptying were then analysed to yield values for: (a) the period before the appearance of isotope in the proximal small intestine (lag p e r i ~ d )(b) , ~ the time taken for half of the isotope to empty from the stomach (t,,,), and (c) tII2 minus lag period, which gives an indication of the rate of emptying. Similarly, the profiles of proximal stomach emptying were analysed to yield values for: (a) the time taken for 5 YO of the isotope to empty from the proximal stomach (t5yoprox), which gives an indication of proximal stomach retention, (b)the time taken for 50 % of the isotope to empty from the proximal stomach (t50%prox), and (c) t,oyo ),,, minus t5%prox, which gives an indication of rate of emptying from the proximaf stomach. Statistical analysis The analysis was performed using analysis of variance allowing for effects due to subjects, treatment periods and treatments7For each analysis, an additional test for treatment by period interaction was performed as was a test for the carryover effect of treatment from one period to the next. The difference between placebo and each treatment was estimated in each analysis, together with 95 % C.I. Twosided f-tests were used to assess the significance of these effect^.^
L. A. H O U G H T O N et al.
688
Table 1. Effect of sumatriptan and metoclopramide on the emptying of a liquid meal from the stomach
Lag period (min) Mean fS.D. Mean difference from placebo (95 % C.I.) P f,,2 b i n ) Mean fS.D. Mean difference from placebo (95% C.I.) P fI,2 - lag (min) Mean S.D. Mean difference from placebo (95 % C.I.) P
Placebo
Sumatriptan
21k10
35f15 - 14(-21, - 7)
76k33
55f28
Metoclopramide
< 0.001
0.013
96k40 - 20( - 47,7)
5 9 1 19 17(- 10,44)
0.140
0.213
61f38 - 6( - 30,19)
47f 19 8( - 17,32)
0.630
0.5 12
Table 2. Effect of sumatriptan and metoclopramide on the emptying of a liquid meal from the proximal stomach Placebo
Sumatriptan
Metoclopramide
25&14
43f12 - 18(- 28, - 8)
9( - 2,19)
0.003
0.091
43k39 -3( -24,17)
32 f12 7( - 13,28)
0.736
0.45 7
~~
(f~y+rox)(mid Mean fS.D. Mean difference from placebo (95% C.I.)
P -
f5 %prox(min) Mean fS.D. Mean difference from placebo (95% CJ.)
f50%prox
16511
P
39k13
RESULTS Under control conditions the soup emptied slowly (t,,, -lag period = 55 $-28 min; meanfS.D.) after an initial lag period of between 6 and 40 min (Table 1 & Figure la). Administration of metoclopramide (10 mg i.v.) significantly decreased the lag period, but did not significantly alter the characteristics of the emptying phase from the whole stomach (tI,z - lag period), compared with placebo (Table I). This reduced the half-time for emptying from the whole stomach (f1,J, though not
S U M A T R I P T A N A N D LIQUID GASTRIC EMPTYING
689
100 -
-
80
-
60
-
40
-
20
-
0
0
sumatriptan metoclopramide control
40
80
120
160
loo[80
a
0
-0 0
Figure 1. Emptying from the (a) whole, (b)proximal and (c) distal stomach for a fatty liquid test meal after intravenous administration of 3 mg sumatriptan 10 mg metoclopramide and saline control. Results are expressed as means S.E.M.
*
I
I
I
I
40
80
120
160
Time (min)
significantly; and was associated with a trend towards reduced retention of isotope (f5%prox)but no change in the rate of emptying from the proximal stomach (t50%prox minus t50hprox) (Tables 1 and 2, Figure 1b). The number of counts in the distal stomach were unaffected by administration of metoclopramide (Figure Ic). 36
BAP 6
690
L. A. H O U G H T O N et al.
Conversely, administration of sumatriptan ( 3 mg i.v.) significantly increased the lag period, tending to increase the half-time for emptying from the whole stomach (f1,J compared with placebo (Table 1 & Figure la); and was associated but no change in rate of with significantly prolonged retention of counts (t50,0prox) minus t,, ),,, from the proximal stomach (Tables I, 2 Figure Ib). emptying (t50%prox Again, the characteristics ofthe emptying phase from the whole stomach [t,,, -lag] and the number of counts in the distal stomach were unaffected by administration of sumatriptan (Table 1 & Figure lc).
Side-effects Ten out of the 12 subjects experienced side-effects associated with the intravenous infusion of sumatriptan. These occurred within 1 to 11 min of the start of the i.v. infusion and lasted between 5 and 30 min. The side-effects included pain at the top of the head, tingling around the forehead and/or body, lightheadedness, nausea and feelings of bodily warmth. These are characteristic of sumatriptan. Two of the subjects also felt lightheaded and nauseated in association with the intravenous infusion of metoclopramide. This occurred within 10 minutes of the start of the i.v. infusion and lasted no longer than 10 min. None of the volunteers experienced any side-effects during or after the i.v. infusion of the saline control. DISCUSSION This study investigated the effect of a selective 5-HT1-like agonist sumatriptan, and metoclopramide, on the rate of gastric emptying of a fatty liquid test meal in normal healthy subjects. A fatty liquid test meal was chosen in preference to a more bland liquid test meal, so that the rate of gastric emptying was slow and any prokinetic properties possessed by the drugs might be detected more easily. As expected metoclopramide accelerated gastric emptying, confirming previous studies;’ though the present study showed that this acceleration in gastric emptying is associated with a decrease in the lag period rather than a change in the slope of emptying, and with a tendency to reduced retention of liquid in the proximal stomach but no change in distal stomach content. Most previous studies investigating the effect of metoclopramide on the emptying of liquid meals from the stomach in normal healthy subjects have not attempted to identify the lag phase,’ making it difficult to say whether the acceleration in gastric emptying is due to a decrease in the lag phase, increase in slope of emptying or both. One study, however, did report a decrease in the lag period but no change in the slope of emptying of a solid meal after oral administration of 10mg metoclopramide in patients with diabetes mellitus.’ Contrary to our expectations, intravenous sumatriptan delayed gastric emptying of a nutritious liquid test meal in human subjects. This effect was related to an increase in the lag period and increased retention of the liquid in the proximal
S U M A T R I P T A N A N D LIQUID GASTRIC EMPTYING
691
stomach, but again there was no change in the characteristics of the emptying phase from the whole or proximal stomach, or in distal stomach content. The forces responsible for the increased retention of liquid in the proximal stomach cannot be deduced from this study, but it may be related to either a reduction in proximal stomach tone, reduced distal stomach contractility, or both. There have been no studies to date investigating the effect of sumatriptan on human proximal and distal stomach contractility. The observation that sumatriptan causes a delay in gastric emptying in normal healthy subjects but improves symptoms in migraine sufferers, even when given late in an attack, suggests that an acceleration in gastric emptying may not be a crucial factor in the treatment of nausea and vomiting associated with migraine. Perhaps sumatriptan acts via a central mechanism to abolish symptoms of nausea and vomiting associated with migraine even though it may have a direct inhibitory effect on gastric motility. ACKNOWLEDGEMENTS
This work was funded by Glaxo Group Research Ltd. REFERENCES 1 Saxena P R. Selective vasoconstriction in
tillation camera and computer system. Gut
carotid vascular bed by methysergide: possible relevance to its anti-migraine action. Eur J Pharm 1974; 27: 99-105. 2 Saxena P R, de Vlaam-Schluter G M. Role of some biogenic substances in migraine and relevant mechanisms in anti-migraine action of ergotamine. Studies in an experimental model of migraine. Headache 1974; 13:
1983; 24: 1117-25. 6 Collins P J, Horowitz M, Shearman D J C, et al. Correction for tissue attenuation in
142-63. 3 Lance J W, Chairman. 5HT,-like receptor
agonist as a novel approach to the treatment of acute migraine : General discussion. Cephalalgia 1989; 9 (Suppl. 9); 97-101. 4 Houghton L A, Mangnall Y F, Read N W. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990; 31: 1226-9. 5 Collins P J, Horowitz M, Cook D J, ef al. Gastric emptying in normal subjects-a reproducible technique using a single scin-
radionuclide gastric emptying studies: a comparison of a lateral image method and a geometric mean method. Br J Radio1 1984; 5 7 : 689-95. 7 Jones B, Kanward M G. Design and analysis of cross-over trials. London: Chapman & Hall 1989; 189-241. 8 Reynolds J C. Prokinetic agents: a key in
future of gastroenterology. In: Ouyang A ed. Gastroenterology Clinics of North America. Motility disorders. Philadelphia: W. B. Saunders, 1989; Vol. 18, No. 2, pp. 43 7-5 7. 9 Loo F D, Palmer D W, Soergel K H, ef al.
Gastric emptying in patients with diabetes mellitus. Gastroenterology 1984; 86: 48594.
36-2
Effect of sumatriptan, a new selective 5HT,-like agonist, on liquid gastric emptying in man
L. A. H O U G H T O N " , P. FOWLERt, 0.N. KEENEt & N. W. READ* * Sub-Department of Gastrointestinal Physiology and Nutrition, University of Shefield, Shefield, and t Glaxo Group Research Ltd, Park Road, Ware, Hertfordshire, U K Accepted for publication 13 July 1992
SUMMARY
Paired studies were carried out on 12 healthy male subjects to compare the effect of intravenous doses of the 5-HT,-like agonist sumatriptan (GR43175; 3 mg), 10 mg metoclopramide and saline control on the rate of gastric emptying of a radiolabelled liquid test-meal. Intravenous administration of metoclopramide accelerated gastric emptying by decreasing the lag period, while intravenous administration of sumatriptan delayed gastric emptying by increasing the lag period. The observation that sumatriptan causes a delay in gastric emptying in normal healthy volunteers, but relieves nausea and vomiting during migraine attacks, suggests that sumatriptan may be acting via a central mechanism to relieve symptoms of nausea and vomiting associated with migraine. INTRODUCTION Sumatriptan is a new selective 5-HT1-like agonist which has been shown to be effective in the treatment of migraine. Its mechanism of action in man is unknown, but studies carried out in both cats and dogs suggest that sumatriptan might be acting by selectively constricting the arteriovenous anastomoses." Correspondence to: Dr L. A. Houghton, Department of Medicine, University Hospital of South Manchester, Nell Lane, Didsbury, Manchester M20 8LR, UK. 685
686
L.A. H O U G H T O N
ef al.
Administration of sumatriptan (0.3-1.0 mg/kg p.0.) accelerates gastric emptying in the rat3 and since migraine is associated with nausea, vomiting and slow gastric emptying, the purpose of this study was to test whether sumatriptan might help to relieve symptoms of nausea and vomiting during migraine attacks by accelerating gastric emptying in humans. Paired gamma camera studies were therefore carried out in 12 healthy male subjects to investigate the effect of sumatriptan and metoclopramide (a positive control) on the rate of gastric emptying of a fatty liquid-test meal. MATERIALS A N D M E T H O D S Subjects Studies were carried out on 12 healthy male subjects, aged between 20 and 39 years. Each subject underwent a full medical examination and laboratory investigations of blood and urine before entering the study, and in each case the results of these investigations were normal. All subjects gave their fully informed consent for the study to be carried out. The equipment conformed to the safety standards laid down by the Department of Health and the study was carried out in accordance with the Declaration of Helsinki and with approval of the Ethics Sub-committee of the Shefield Southern District Hospitals. Experimental protocol The subjects were studied on three separate occasions separated by periods of at least 1 week. O n each occasion, they were given either intravenous 3 mg sumatriptan (Glaxo, Ware, Herts, UK), 10 mg metoclopramide (Beechams, Harlow, Essex, UK), or saline control. The order of administration of the drugs and saline control was randomized and double-blind. Subjects fasted for at least 12 h before each study. No alcohol was permitted for 24 h before each study and cigarette smoking was not allowed on the study day. O n the day of the study a cannula was inserted into a suitable forearm vein for infusion of the drug or placebo. The subject then sat vertically against a posteriorly positioned gamma camera (Model 1201 Pho/Gamma Scintillation Camera, Nuclear-Chicago, Europa NV, Amsterdam, The Netherlands) and one of the treatments infused intravenously over 10 min at a rate of 1ml/min. At the end of the i.v. infusion the indwelling cannula was removed and the subjects drank 300 ml of warmed (approx 40 "C) soup (Beef Consommg, Campbell Grocery Products, Kings Lynn, Norfolk containing 3 g fat, 1.2 g carbohydrate, 1.8 g protein) to which had been added 30 g (228 kcal) margarine (Suma Sunflower Margarine, Halifax, West Yorkshire)and 1.89 MBq 99mTechnetium tin colloid. The margarine was mixed into the soup using a blender and studies in vitvo have shown that the fat does not separate out after a period of 3 h, even when 0.1 M hydrochloric acid was added.
SUMATRIPTAN A N D L I Q U I D GASTRIC EMPTYING
687
This soup has been used before in previous studies4 and is considered appetizing. All subjects consumed the soup within one minute.
Measurement of gasfric emptying Images of the distribution of the radioactivity in the abdominal cavity were collected over consecutive 2-min periods for the first 45 frames and then over consecutive 5-min periods for a further 1 2 frames. The total period of data collection was 150 min. Data collection began at the start of liquid ingestion. At the end of the study, a further 1.89 MBq 99"Technetium-tin colloid in 150 ml water was given orally and a left lateral image of the stomach was acquired over 5 min so that the images of the stomach, obtained by the posteriorly positioned gamma camera could be corrected for tissue attenuation caused by the isotope moving away from the gamma camera as the meal e m ~ t i e d , ~ , ~ To analyse the gamma camera records, the position of the stomach was identified from the images obtained during the first 10 min of the study and outlined using a cursor. Sub-areas were also defined to enclose the proximal (fundus and . ~ computer then body of stomach) and distal (antrum) regions of the ~ t o m a c hThe extracted the counts from each region of interest, corrected them for decay and tissue attenuation and expressed them as a percentage of the counts obtained in the gastric region immediately after ingestion of the meal. These figures were then used to construct profiles of the proportion of counts in the whole stomach and in each sub-region throughout the study. The profiles of whole stomach emptying were then analysed to yield values for: (a) the period before the appearance of isotope in the proximal small intestine (lag p e r i ~ d )(b) , ~ the time taken for half of the isotope to empty from the stomach (t,,,), and (c) tII2 minus lag period, which gives an indication of the rate of emptying. Similarly, the profiles of proximal stomach emptying were analysed to yield values for: (a) the time taken for 5 YO of the isotope to empty from the proximal stomach (t5yoprox), which gives an indication of proximal stomach retention, (b)the time taken for 50 % of the isotope to empty from the proximal stomach (t50%prox), and (c) t,oyo ),,, minus t5%prox, which gives an indication of rate of emptying from the proximaf stomach. Statistical analysis The analysis was performed using analysis of variance allowing for effects due to subjects, treatment periods and treatments7For each analysis, an additional test for treatment by period interaction was performed as was a test for the carryover effect of treatment from one period to the next. The difference between placebo and each treatment was estimated in each analysis, together with 95 % C.I. Twosided f-tests were used to assess the significance of these effect^.^
L. A. H O U G H T O N et al.
688
Table 1. Effect of sumatriptan and metoclopramide on the emptying of a liquid meal from the stomach
Lag period (min) Mean fS.D. Mean difference from placebo (95 % C.I.) P f,,2 b i n ) Mean fS.D. Mean difference from placebo (95% C.I.) P fI,2 - lag (min) Mean S.D. Mean difference from placebo (95 % C.I.) P
Placebo
Sumatriptan
21k10
35f15 - 14(-21, - 7)
76k33
55f28
Metoclopramide
< 0.001
0.013
96k40 - 20( - 47,7)
5 9 1 19 17(- 10,44)
0.140
0.213
61f38 - 6( - 30,19)
47f 19 8( - 17,32)
0.630
0.5 12
Table 2. Effect of sumatriptan and metoclopramide on the emptying of a liquid meal from the proximal stomach Placebo
Sumatriptan
Metoclopramide
25&14
43f12 - 18(- 28, - 8)
9( - 2,19)
0.003
0.091
43k39 -3( -24,17)
32 f12 7( - 13,28)
0.736
0.45 7
~~
(f~y+rox)(mid Mean fS.D. Mean difference from placebo (95% C.I.)
P -
f5 %prox(min) Mean fS.D. Mean difference from placebo (95% CJ.)
f50%prox
16511
P
39k13
RESULTS Under control conditions the soup emptied slowly (t,,, -lag period = 55 $-28 min; meanfS.D.) after an initial lag period of between 6 and 40 min (Table 1 & Figure la). Administration of metoclopramide (10 mg i.v.) significantly decreased the lag period, but did not significantly alter the characteristics of the emptying phase from the whole stomach (tI,z - lag period), compared with placebo (Table I). This reduced the half-time for emptying from the whole stomach (f1,J, though not
S U M A T R I P T A N A N D LIQUID GASTRIC EMPTYING
689
100 -
-
80
-
60
-
40
-
20
-
0
0
sumatriptan metoclopramide control
40
80
120
160
loo[80
a
0
-0 0
Figure 1. Emptying from the (a) whole, (b)proximal and (c) distal stomach for a fatty liquid test meal after intravenous administration of 3 mg sumatriptan 10 mg metoclopramide and saline control. Results are expressed as means S.E.M.
*
I
I
I
I
40
80
120
160
Time (min)
significantly; and was associated with a trend towards reduced retention of isotope (f5%prox)but no change in the rate of emptying from the proximal stomach (t50%prox minus t50hprox) (Tables 1 and 2, Figure 1b). The number of counts in the distal stomach were unaffected by administration of metoclopramide (Figure Ic). 36
BAP 6
690
L. A. H O U G H T O N et al.
Conversely, administration of sumatriptan ( 3 mg i.v.) significantly increased the lag period, tending to increase the half-time for emptying from the whole stomach (f1,J compared with placebo (Table 1 & Figure la); and was associated but no change in rate of with significantly prolonged retention of counts (t50,0prox) minus t,, ),,, from the proximal stomach (Tables I, 2 Figure Ib). emptying (t50%prox Again, the characteristics ofthe emptying phase from the whole stomach [t,,, -lag] and the number of counts in the distal stomach were unaffected by administration of sumatriptan (Table 1 & Figure lc).
Side-effects Ten out of the 12 subjects experienced side-effects associated with the intravenous infusion of sumatriptan. These occurred within 1 to 11 min of the start of the i.v. infusion and lasted between 5 and 30 min. The side-effects included pain at the top of the head, tingling around the forehead and/or body, lightheadedness, nausea and feelings of bodily warmth. These are characteristic of sumatriptan. Two of the subjects also felt lightheaded and nauseated in association with the intravenous infusion of metoclopramide. This occurred within 10 minutes of the start of the i.v. infusion and lasted no longer than 10 min. None of the volunteers experienced any side-effects during or after the i.v. infusion of the saline control. DISCUSSION This study investigated the effect of a selective 5-HT1-like agonist sumatriptan, and metoclopramide, on the rate of gastric emptying of a fatty liquid test meal in normal healthy subjects. A fatty liquid test meal was chosen in preference to a more bland liquid test meal, so that the rate of gastric emptying was slow and any prokinetic properties possessed by the drugs might be detected more easily. As expected metoclopramide accelerated gastric emptying, confirming previous studies;’ though the present study showed that this acceleration in gastric emptying is associated with a decrease in the lag period rather than a change in the slope of emptying, and with a tendency to reduced retention of liquid in the proximal stomach but no change in distal stomach content. Most previous studies investigating the effect of metoclopramide on the emptying of liquid meals from the stomach in normal healthy subjects have not attempted to identify the lag phase,’ making it difficult to say whether the acceleration in gastric emptying is due to a decrease in the lag phase, increase in slope of emptying or both. One study, however, did report a decrease in the lag period but no change in the slope of emptying of a solid meal after oral administration of 10mg metoclopramide in patients with diabetes mellitus.’ Contrary to our expectations, intravenous sumatriptan delayed gastric emptying of a nutritious liquid test meal in human subjects. This effect was related to an increase in the lag period and increased retention of the liquid in the proximal
S U M A T R I P T A N A N D LIQUID GASTRIC EMPTYING
691
stomach, but again there was no change in the characteristics of the emptying phase from the whole or proximal stomach, or in distal stomach content. The forces responsible for the increased retention of liquid in the proximal stomach cannot be deduced from this study, but it may be related to either a reduction in proximal stomach tone, reduced distal stomach contractility, or both. There have been no studies to date investigating the effect of sumatriptan on human proximal and distal stomach contractility. The observation that sumatriptan causes a delay in gastric emptying in normal healthy subjects but improves symptoms in migraine sufferers, even when given late in an attack, suggests that an acceleration in gastric emptying may not be a crucial factor in the treatment of nausea and vomiting associated with migraine. Perhaps sumatriptan acts via a central mechanism to abolish symptoms of nausea and vomiting associated with migraine even though it may have a direct inhibitory effect on gastric motility. ACKNOWLEDGEMENTS
This work was funded by Glaxo Group Research Ltd. REFERENCES 1 Saxena P R. Selective vasoconstriction in
tillation camera and computer system. Gut
carotid vascular bed by methysergide: possible relevance to its anti-migraine action. Eur J Pharm 1974; 27: 99-105. 2 Saxena P R, de Vlaam-Schluter G M. Role of some biogenic substances in migraine and relevant mechanisms in anti-migraine action of ergotamine. Studies in an experimental model of migraine. Headache 1974; 13:
1983; 24: 1117-25. 6 Collins P J, Horowitz M, Shearman D J C, et al. Correction for tissue attenuation in
142-63. 3 Lance J W, Chairman. 5HT,-like receptor
agonist as a novel approach to the treatment of acute migraine : General discussion. Cephalalgia 1989; 9 (Suppl. 9); 97-101. 4 Houghton L A, Mangnall Y F, Read N W. Effect of incorporating fat into a liquid test meal on the relation between intragastric distribution and gastric emptying in human volunteers. Gut 1990; 31: 1226-9. 5 Collins P J, Horowitz M, Cook D J, ef al. Gastric emptying in normal subjects-a reproducible technique using a single scin-
radionuclide gastric emptying studies: a comparison of a lateral image method and a geometric mean method. Br J Radio1 1984; 5 7 : 689-95. 7 Jones B, Kanward M G. Design and analysis of cross-over trials. London: Chapman & Hall 1989; 189-241. 8 Reynolds J C. Prokinetic agents: a key in
future of gastroenterology. In: Ouyang A ed. Gastroenterology Clinics of North America. Motility disorders. Philadelphia: W. B. Saunders, 1989; Vol. 18, No. 2, pp. 43 7-5 7. 9 Loo F D, Palmer D W, Soergel K H, ef al.
Gastric emptying in patients with diabetes mellitus. Gastroenterology 1984; 86: 48594.
36-2
