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Treatment of Ureteral Colic with Intravenous Indomethacin
0022-5347 /78/1206-0676$0. 200/0 Vol. 120, December Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
TREATMENT OF URETERAL COLIC WITH INTRAVENOUS INDOMETHACIN DAN HOLMLUND
AND
JAN-GUNNAR SJODIN
From the Departments of General Surgery and Urology, Regionssjukhuset i Umea, University of Umea, Umea, Sweden
ABSTRACT
A randomized prospective double-blind study of the analgesic effect of 50 mg. intravenous indomethacin, a prostaglandin synthesis inhibitor, was done on 47 consecutive patients with acute ureteral colic. The placebo used was 5 mg. intravenous riboflavin because of the same color as indomethacin. Indomethacin provided complete relief in 78 per cent of the cases, while riboflavin provided relief in 30 per cent. The difference is statistically significant. No side effects were observed with indomethacin. The pressure of the urine in the urinary tract above an obstructing ureteral stone tends to increase. This increase in pressure is accompanied by high tension in the pelvic and ureteral wall, causing severe pain, ureteral colic. 1• 2 Even a moderate reduction in pressure above the stone will result in a significant decrease in tension in the renal pelvic wall2 and, consequently, in pain. Such a reduction of pressure can be achieved by 1) improved flow of urine through the ureter or 2) reduction of urine production. Improved flow of urine is achieved, of course, by removal of the stone but can also follow antiphlogistic therapy, which reduces edema in the ureteral wall around the stone. 2 • 3 However, investigators who tried to treat ureteral colic with spasmolytic drugs failed, 4 • 5 which shows that no improvement ofureteral flow was achieved with such therapy. An increase in the renal pelvic pressure above an obstructing ureteral stone stimulates the synthesis of prostaglandin E 2 in the renal medulla. 5- 7 Prostaglandin E 2 improves renal blood flow and has a diuretic effect (sodium diuresis). 8' 9 The administration of indomethacin, * a potent inhibitor of the synthesis ofprostaglandin, causes a significant (>50 per cent) reduction of the diuresis within 15 minutes. ,o, 11 Indometha cin... als.Q_has a _;Ye)] documente.d antipb)ogistic eff'ect that I®Y/ improve the ureteral flow around a ur eral stone s d a ous herefore, there is e r reason to y an e !relieve t a indomethacm is usefu m e treatment of pa..=hentswith ureteral cohc. The aim of our stuuy 1s to verify this
~
MATERIAL AND METHODS
way. During the 60 minutes no other analgesic was used. The code was kept by the pharmaceutical chemist. In all cases an IVP was made during or immediately after registration of the effect of therapy. For statistical analysis the chi-square test was used. RESULTS
Complete relief of pain was achieved in 21 of 27 patients who received indomethacin as the first injection. Only 6 of 20 patients in the placebo group had complete relief. This difference is significant (p < 0.01) (table 1). The 20 patients who had incomplete or no relief of pain after the first injection were given the second injection. In 10 of 14 patients from the placebo group indomethacin provided complete relief of pain. In 1 of 6 patients from the indomethacin group complete relief of pain was observed after the placebo injection. In 24 of the 31 patients who had complete relief of pain with indomethacin the effect was registered within 20 minutes. In 19 of these patients there was an almost immediate effect (table 2). All patients rendered free of pain were observed for 4 hours. In 1 patient the ureteral colic reappeared during this period. The 4 patients who had been treated with pentazocine during earlier attacks of ureteral colic preferred the new drug because "the pain disappeared completely and no nausea or drowsiness was experienced". Pulse rate and blood pressure remained unchanged during and after the administration of indomethacin or riboflavin. No gastric pain or other side effects were observed.
Patients with ureteral colic who were admitted to our hospital from November 1976 to January 1977 are included in the study. Therapy was started when the diagnosis ofureteral colic was made on the basis of history and clinical examination. Patients were excluded if the diagnosis could not be verified by an excretory urogram (IVP). In all, 47 patients were included in the study, each with a verified obstructing ureteral stone. Therapy. Two coded ampules, A and B, were prepared for each patient. One ampule contained 50 mg. indomethacin m ixed with 5 ml. sterile water and the other one contained 5 mg. riboflavin mixed with 5 ml. isotonic sodium chloride. First the contents of ampule A was administered intravenously. Every 5 minutes the blood pressure, pulse rate and the eventual analgesic effect were registered. If complete relief of pain was achieved within 30 minutes or less the next ampule was not used. Otherwise, the contents in ampule B was administered and the effect was registered in the same Accepted for publication March 31, 1978. * Durnex Ltd., Prags Bud. 37, Dk 2300, Copenhagen S, Denmark .
676
DISCUSSION
Our study reveals that intravenous indomethacin can be used successfully in the treatment of ureteral colic. It is accepted generally that the pain in ureteral colic is a result of increased pressure of urine above the stone. 1• 2 Consequently, our results prove that intravenous indomethacin reduces this pressure. Indomethacin reduces diuresis and renal blood flow in the non-obstructed kidney. 10• 11 Its effect on renal blood flow and diuresis in an obstructed kidney has yet to be elucidated. However, elevated pelvioureteral pressure releases prostaglandin E 2 in the kidney. Consequently, indomethacin (an inhibitor of the synthesis of prostaglandin) should have a more pronounced effect in such a situation. In the present study 19 patients experienced almost immediate relief of pain. It seems probable that this effect was mediated via a reduction of renal blood flow, resulting in a simultaneous reduct ion of the pelvioureteral pressure. In other patients relief of pain occurred within 10 to 30 minutes. It seems probable that in
677
INDOMETHACIN IN URETERAL COLIC TABLE
1. Effect ofindomethacin or placebo in 47 cases of ureteral colic Incomplete Relief
Complete Relief
Injection 1 Indomethacin, 27 pts. Placebo, 20 pts.
21 6
6
14
lnjection2 Indomethacin, 14 pts. Placebo, 6 pts.
TABLE
10
4 5
1
2. Interval between administration ofindomethacin and
complete relief of pain Mins.
No. Pts.
<10 11-20 21-30
19 5 7
these patients the reduction of the pelvioureteral pressure was caused by a reduction of the diuresis known to appear in the first 15 minutes after the administration of indomethacin. 11 The dose of indomethacin used in most patients in our study was less than 1 mg./kg. body weight. Usberti and associates used 4 mg./kg. body weight in an investigation of the effect of indomethacin on the renal function in man. 10 In most patients the small dose used in our study had a satisfactory effect but it also is possible that the patients who did not experience relief of pain might have been helped by a larger dose. Therefore, we plan to use the same dose in a followup study but repeat the administration of 50 mg. indomethacin ifno or little effect is achieved with the first injection. Kubacz and Catchpole observed relief of pain in patients with ureteral colic after administration of phentolamine, an a-receptor blockade that caused a reduction of the diastolic blood pressure by 10 mm. Hg. 12 It seems probable that such a reduction of blood pressure also caused a decrease of renal blood flow and of the urine production, thus reducing the pelvioureteral pressure above the stone. It is probable that the effect of indomethacin on ureteral colic is chiefly a result of changes in the kidney but its possible effects on the ureter must be considered. The antiphlogistic effect of indomethacin on the edematous ureteral wall around the stone may improve the ureteral flow and reduce the pressure. However, it is difficult to explain the immediate relief of pain in this way. The effect of prostaglandin9 and of indomethacin' 3 on the smooth muscle of the ureter is not known. However, it is not probable that the flow of urine through an obstructed and distended ureter is influenced by any effect on the smooth muscle. 1• 2 Analgesics make the patients less conscious of pain but often leave them with a dull feeling of discomfort or with moderate pain. The patients in our study who were able to compare the effect of a strong analgesic to that of indomethacin preferred the latter, which provided complete relief of pain.
In general, indomethacin has a moderate analgesic effect. 14 This effect probably is not strong enough to cause complete relief of pain in patients with severe ureteral colic. Therefore, it seems probable that the effect of indomethacin on ureteral colic is chiefly caused by the effect on the kidney and, to a lesser extent, by an effect on the ureter or a general analgesic effect. Metamizol, which for years was used successfully in the treatment of patients with ureteral colic, is a strong inhibitor of the synthesis of prostaglandin but has been reported to cause agranulocytosis. Our study shows that indomethacin is as effective and probably less dangerous than metamizol, no side effects being observed. However, further studies of eventual side effects of intravenous administration of indomethacin are needed before one definitely and without any reservations can recommend it for use in the treatment of patients with ureteral colic.
p
REFERENCES
1. Kiil, F.: The FCJction of the Ureter and Renal Pelvis. Philadelphia: W. B. Saunders Co., p. 142, 1957. 2. Holmlund, D.: Ureteral stones. An experimental and clinical study of the mechanism of the passage and arrest of ureteral stones. Scand. J. Urol. Nephrol., suppl. 1, 1968. 3. Nygard, A. and Bjorneby, 8.: Oxyphenbutazone in the treatment of acute ureteral stone disease. Scand. J. Urol. Nephrol., 9: 36, 1975. 4. Redecker, K. D.: Spasmoanalgetische Behandlung in der Urologie. Med. Welt., 33: 1703, 1962. 5. Gilmore, J. P.: Renal vascular resistance during elevated ureteral pressure. Circ. Res., suppl 1, 15: 148, 1964. 6. Schramm, L. P. and Carlson, D. E.: Inhibition of renal vasoconstriction by elevated ureteral pressure. Amer. J. Physiol., 228: 1126, 1975. 7. Abe, Y., Kishimoto, T., Yamamoto, K. and Ueda, J.: Intrarenal distribution of blood flow during ureteral and venous pressure elevation. Amer. J. Physiol., 224: 746, 1973. 8. Johnston, H. H., Herzog, J. P. and Lauler, D. P.: Effect of prostaglandin El on renal hemodynamics, sodium and water excretion. Amer. J. Physiol., 231: 939, 1967. 9. Horton, E. W.: Hypotheses on physiological roles of prostaglandins. Physiol. Rev., 49: 122, 1969. 10. Usberti, M., Mileti, M. and Maiorca, R.: Effect ofindomethacin on renal function. Abstract. Kid. Int., 7: 197, 1975. 11. Feigen, L. P., Klainer, E., Chapnick, B. M. and Kadowitz, P. J.: The effect ofindomethacin on renal function in pentobarbitalanesthetized dogs. J. Pharmacol. Exp. Ther., 198: 457, 1976. 12. Kubacz, G. J. and Catchpole, B. N.: The role of adrenergic blockade in the treatment ofureteral colic. J. Urol., 107: 949, 1972. 13. McGiff, J. C., Terragno, N. A. and Itskovitz, H. D.: Role of prostaglandins as revealed by inhibitors of prostaglandin synthetase. In: Prostaglandin Synthetase Inhibitors; Their Effect on Physiological Functions and Pathological States. Edited by H.J. Robinson and J. R. Vane. New York: Raven Press, p. 259, 1974. 14. Vaage, J.: Acetylsalicylsyre og prostaglandiner. Kan hemming av prostaglandinsyntese forklare Virkningen av 'aspirinlignende' medikamenter. T. Norsk. Laegeforen., 92: 1727, 1976.
THE JOURNAL OF UROLOGY
Copyright © 1978 by The Williams & Wilkins Co.
TREATMENT OF URETERAL COLIC WITH INTRAVENOUS INDOMETHACIN DAN HOLMLUND
AND
JAN-GUNNAR SJODIN
From the Departments of General Surgery and Urology, Regionssjukhuset i Umea, University of Umea, Umea, Sweden
ABSTRACT
A randomized prospective double-blind study of the analgesic effect of 50 mg. intravenous indomethacin, a prostaglandin synthesis inhibitor, was done on 47 consecutive patients with acute ureteral colic. The placebo used was 5 mg. intravenous riboflavin because of the same color as indomethacin. Indomethacin provided complete relief in 78 per cent of the cases, while riboflavin provided relief in 30 per cent. The difference is statistically significant. No side effects were observed with indomethacin. The pressure of the urine in the urinary tract above an obstructing ureteral stone tends to increase. This increase in pressure is accompanied by high tension in the pelvic and ureteral wall, causing severe pain, ureteral colic. 1• 2 Even a moderate reduction in pressure above the stone will result in a significant decrease in tension in the renal pelvic wall2 and, consequently, in pain. Such a reduction of pressure can be achieved by 1) improved flow of urine through the ureter or 2) reduction of urine production. Improved flow of urine is achieved, of course, by removal of the stone but can also follow antiphlogistic therapy, which reduces edema in the ureteral wall around the stone. 2 • 3 However, investigators who tried to treat ureteral colic with spasmolytic drugs failed, 4 • 5 which shows that no improvement ofureteral flow was achieved with such therapy. An increase in the renal pelvic pressure above an obstructing ureteral stone stimulates the synthesis of prostaglandin E 2 in the renal medulla. 5- 7 Prostaglandin E 2 improves renal blood flow and has a diuretic effect (sodium diuresis). 8' 9 The administration of indomethacin, * a potent inhibitor of the synthesis ofprostaglandin, causes a significant (>50 per cent) reduction of the diuresis within 15 minutes. ,o, 11 Indometha cin... als.Q_has a _;Ye)] documente.d antipb)ogistic eff'ect that I®Y/ improve the ureteral flow around a ur eral stone s d a ous herefore, there is e r reason to y an e !relieve t a indomethacm is usefu m e treatment of pa..=hentswith ureteral cohc. The aim of our stuuy 1s to verify this
~
MATERIAL AND METHODS
way. During the 60 minutes no other analgesic was used. The code was kept by the pharmaceutical chemist. In all cases an IVP was made during or immediately after registration of the effect of therapy. For statistical analysis the chi-square test was used. RESULTS
Complete relief of pain was achieved in 21 of 27 patients who received indomethacin as the first injection. Only 6 of 20 patients in the placebo group had complete relief. This difference is significant (p < 0.01) (table 1). The 20 patients who had incomplete or no relief of pain after the first injection were given the second injection. In 10 of 14 patients from the placebo group indomethacin provided complete relief of pain. In 1 of 6 patients from the indomethacin group complete relief of pain was observed after the placebo injection. In 24 of the 31 patients who had complete relief of pain with indomethacin the effect was registered within 20 minutes. In 19 of these patients there was an almost immediate effect (table 2). All patients rendered free of pain were observed for 4 hours. In 1 patient the ureteral colic reappeared during this period. The 4 patients who had been treated with pentazocine during earlier attacks of ureteral colic preferred the new drug because "the pain disappeared completely and no nausea or drowsiness was experienced". Pulse rate and blood pressure remained unchanged during and after the administration of indomethacin or riboflavin. No gastric pain or other side effects were observed.
Patients with ureteral colic who were admitted to our hospital from November 1976 to January 1977 are included in the study. Therapy was started when the diagnosis ofureteral colic was made on the basis of history and clinical examination. Patients were excluded if the diagnosis could not be verified by an excretory urogram (IVP). In all, 47 patients were included in the study, each with a verified obstructing ureteral stone. Therapy. Two coded ampules, A and B, were prepared for each patient. One ampule contained 50 mg. indomethacin m ixed with 5 ml. sterile water and the other one contained 5 mg. riboflavin mixed with 5 ml. isotonic sodium chloride. First the contents of ampule A was administered intravenously. Every 5 minutes the blood pressure, pulse rate and the eventual analgesic effect were registered. If complete relief of pain was achieved within 30 minutes or less the next ampule was not used. Otherwise, the contents in ampule B was administered and the effect was registered in the same Accepted for publication March 31, 1978. * Durnex Ltd., Prags Bud. 37, Dk 2300, Copenhagen S, Denmark .
676
DISCUSSION
Our study reveals that intravenous indomethacin can be used successfully in the treatment of ureteral colic. It is accepted generally that the pain in ureteral colic is a result of increased pressure of urine above the stone. 1• 2 Consequently, our results prove that intravenous indomethacin reduces this pressure. Indomethacin reduces diuresis and renal blood flow in the non-obstructed kidney. 10• 11 Its effect on renal blood flow and diuresis in an obstructed kidney has yet to be elucidated. However, elevated pelvioureteral pressure releases prostaglandin E 2 in the kidney. Consequently, indomethacin (an inhibitor of the synthesis of prostaglandin) should have a more pronounced effect in such a situation. In the present study 19 patients experienced almost immediate relief of pain. It seems probable that this effect was mediated via a reduction of renal blood flow, resulting in a simultaneous reduct ion of the pelvioureteral pressure. In other patients relief of pain occurred within 10 to 30 minutes. It seems probable that in
677
INDOMETHACIN IN URETERAL COLIC TABLE
1. Effect ofindomethacin or placebo in 47 cases of ureteral colic Incomplete Relief
Complete Relief
Injection 1 Indomethacin, 27 pts. Placebo, 20 pts.
21 6
6
14
lnjection2 Indomethacin, 14 pts. Placebo, 6 pts.
TABLE
10
4 5
1
2. Interval between administration ofindomethacin and
complete relief of pain Mins.
No. Pts.
<10 11-20 21-30
19 5 7
these patients the reduction of the pelvioureteral pressure was caused by a reduction of the diuresis known to appear in the first 15 minutes after the administration of indomethacin. 11 The dose of indomethacin used in most patients in our study was less than 1 mg./kg. body weight. Usberti and associates used 4 mg./kg. body weight in an investigation of the effect of indomethacin on the renal function in man. 10 In most patients the small dose used in our study had a satisfactory effect but it also is possible that the patients who did not experience relief of pain might have been helped by a larger dose. Therefore, we plan to use the same dose in a followup study but repeat the administration of 50 mg. indomethacin ifno or little effect is achieved with the first injection. Kubacz and Catchpole observed relief of pain in patients with ureteral colic after administration of phentolamine, an a-receptor blockade that caused a reduction of the diastolic blood pressure by 10 mm. Hg. 12 It seems probable that such a reduction of blood pressure also caused a decrease of renal blood flow and of the urine production, thus reducing the pelvioureteral pressure above the stone. It is probable that the effect of indomethacin on ureteral colic is chiefly a result of changes in the kidney but its possible effects on the ureter must be considered. The antiphlogistic effect of indomethacin on the edematous ureteral wall around the stone may improve the ureteral flow and reduce the pressure. However, it is difficult to explain the immediate relief of pain in this way. The effect of prostaglandin9 and of indomethacin' 3 on the smooth muscle of the ureter is not known. However, it is not probable that the flow of urine through an obstructed and distended ureter is influenced by any effect on the smooth muscle. 1• 2 Analgesics make the patients less conscious of pain but often leave them with a dull feeling of discomfort or with moderate pain. The patients in our study who were able to compare the effect of a strong analgesic to that of indomethacin preferred the latter, which provided complete relief of pain.
In general, indomethacin has a moderate analgesic effect. 14 This effect probably is not strong enough to cause complete relief of pain in patients with severe ureteral colic. Therefore, it seems probable that the effect of indomethacin on ureteral colic is chiefly caused by the effect on the kidney and, to a lesser extent, by an effect on the ureter or a general analgesic effect. Metamizol, which for years was used successfully in the treatment of patients with ureteral colic, is a strong inhibitor of the synthesis of prostaglandin but has been reported to cause agranulocytosis. Our study shows that indomethacin is as effective and probably less dangerous than metamizol, no side effects being observed. However, further studies of eventual side effects of intravenous administration of indomethacin are needed before one definitely and without any reservations can recommend it for use in the treatment of patients with ureteral colic.
p
REFERENCES
1. Kiil, F.: The FCJction of the Ureter and Renal Pelvis. Philadelphia: W. B. Saunders Co., p. 142, 1957. 2. Holmlund, D.: Ureteral stones. An experimental and clinical study of the mechanism of the passage and arrest of ureteral stones. Scand. J. Urol. Nephrol., suppl. 1, 1968. 3. Nygard, A. and Bjorneby, 8.: Oxyphenbutazone in the treatment of acute ureteral stone disease. Scand. J. Urol. Nephrol., 9: 36, 1975. 4. Redecker, K. D.: Spasmoanalgetische Behandlung in der Urologie. Med. Welt., 33: 1703, 1962. 5. Gilmore, J. P.: Renal vascular resistance during elevated ureteral pressure. Circ. Res., suppl 1, 15: 148, 1964. 6. Schramm, L. P. and Carlson, D. E.: Inhibition of renal vasoconstriction by elevated ureteral pressure. Amer. J. Physiol., 228: 1126, 1975. 7. Abe, Y., Kishimoto, T., Yamamoto, K. and Ueda, J.: Intrarenal distribution of blood flow during ureteral and venous pressure elevation. Amer. J. Physiol., 224: 746, 1973. 8. Johnston, H. H., Herzog, J. P. and Lauler, D. P.: Effect of prostaglandin El on renal hemodynamics, sodium and water excretion. Amer. J. Physiol., 231: 939, 1967. 9. Horton, E. W.: Hypotheses on physiological roles of prostaglandins. Physiol. Rev., 49: 122, 1969. 10. Usberti, M., Mileti, M. and Maiorca, R.: Effect ofindomethacin on renal function. Abstract. Kid. Int., 7: 197, 1975. 11. Feigen, L. P., Klainer, E., Chapnick, B. M. and Kadowitz, P. J.: The effect ofindomethacin on renal function in pentobarbitalanesthetized dogs. J. Pharmacol. Exp. Ther., 198: 457, 1976. 12. Kubacz, G. J. and Catchpole, B. N.: The role of adrenergic blockade in the treatment ofureteral colic. J. Urol., 107: 949, 1972. 13. McGiff, J. C., Terragno, N. A. and Itskovitz, H. D.: Role of prostaglandins as revealed by inhibitors of prostaglandin synthetase. In: Prostaglandin Synthetase Inhibitors; Their Effect on Physiological Functions and Pathological States. Edited by H.J. Robinson and J. R. Vane. New York: Raven Press, p. 259, 1974. 14. Vaage, J.: Acetylsalicylsyre og prostaglandiner. Kan hemming av prostaglandinsyntese forklare Virkningen av 'aspirinlignende' medikamenter. T. Norsk. Laegeforen., 92: 1727, 1976.