EnfishJournu/o/ Urology (1990), 65, 576579
0007- I33 1/90/0065 4576/%1000
8 1990 British Journal of Urology
Treatment of Ureteric Colic. Intravenous versus Rectal Administration of Indomethacin I. NISSEN, H. BIRKE, J. B. OLSEN, E. WURTZ,K. LORENTZEN, H. SALOMON, P. LYNGE,P. FLY, T. H. J0RGENSEN. S. SVANE and B. B. NIELSEN Departments of Surgery, Thisted, Esbjerg, Kolding, Holstedbro, Holbaek, Skive, Nykobing Mors, Ssnderborg and Viborg Hospitals; Department of Urology, Gentofte Hospital, Gentofte. Denmark
Summary-A randomised multicentre clinical trial was undertaken to compare the effect on pain of indomethacin administered either intravenously or rectally to 1 16 patients with ureteric colic. Adverse reactions were also assessed. Of the patients receiving the intravenous injection, 4 8 / 5 3 (91%) achieved good pain relief ( i e . no supplementary analgesia was required) 30 min after administration, compared with 4 6 / 6 3 (73%) receiving the enema. Significantly more side effects occurred in the group treated intravenously. It was concluded that indomethacin administered as an enema was less effective than the intravenous form, but it should be regarded as a good alternative in the treatment of ureteric colic.
The pain caused by the passage of a ureteric stone results from increased pelviureteric pressure (Risholm 1954; Kiil, 1957) which produces increased tension in the pelvic and ureteric wall (Holmlund and Svanvik, 1982). Potent inhibitors of prostaglandin synthesis such as indomethacin (Holmlund and Sjodin, 1978) and diclofenac (Lundstam et al., 1982) relieve renal colic effectively when given parenterally. Parenteral administration, however, has the disadvantage of requiring either admission to hospital or the presence of medical staff before pain relief can be achieved. Oral medication is not suitable because of the nausea and vomiting that often accompany acute ureteric colic. A better alternative would seem to be rectal administration, which has none of these disadvantages. Bioavailability studies (Jensen, 1985)have shown comparability between indomethacin 100 mg given as a rectal solution and 50 mg given intravenously. Using these dosages and routes of administration, we assessed indomethacin in terms of efficacy and safety in the treatment of ureteric colic. Accepted for publication 1 I October 1989
Patients and Methods
The inclusion criteria for this multicentre, doubleblind, randomised trial were clinical symptoms of ureteric colic, age range 18 to 75 years, and informed consent. Exclusion criteria are listed in Table 1. Safety was assessed in all patients receiving treatment. The efficacyof the drug was analysed statistically only when the diagnosis had been confirmed either by intravenous urography or by spontaneous passage of the stone. Of the 423 patients registered, 265 were excluded for 1 or more of the reasons listed in Table 1 . There was no statistically significant difference in age, sex and weight of these 265 patients and the 158 who were included in the study. The diagnosis could not be verified in 42/ 158 patients and so the statistical analysis was based on 116 patients; 53 of these received indomethacin intravenously and 63 received it as an enema. There was no statistically significant difference between the 2 groups with respect to age, sex, weight or pretreatment pain score. The medication was prepared shortly before administration. The enema was always given first and the injection (over 5 min) began immediately afterwards.
576
577
URETERIC COLIC AND ADMINISTRATION OF INDOMETHACIN
Table 1 Reasons for Exclusion of 265 patients Reoson
Morphine treatment within 4 h NSAID treatment within 24 h Informed consent not given N o clinical symptoms Age below 18 or above 75 years Peptic ulcer or gastritis Severe heart/lung/kidney disease Analgesia unnecessary NSAID allergy Known or suspected pregnancy Staff pressed for time Already in the study Haemorrhagic diathesis Medication lost Intense pain Recent surgery Malignant hypertension Not known
No. of patients I02 69 48 22 22 19 15 14 10
4 3 2 1 1 I 1 0 I
oj264
39 26 18 8
8 7 6 5 4 2 I 0.8 0.4 0.4 0.4 0.4 0 0.4
Some patients had more than 1 reason for exclusion and not all patients were assessed with regard to all possible reasons.
The intensity of pain was assessed before and 10, 20 and 30min after administration by a visual analogue scale (VAS, 100 mm). Patients were asked at 30min whether or not the pain relief was satisfactory; if not, they were given the analgesic commonly used at that particular hospital. All answers were recorded. Adverse effects were registered on a special form at the time of treatment and a note was made as to whether the complaint was reported spontaneously or elicited by general questioning. Patients were not allowed to drink liquids while the pain persisted. Statistical methods The data were statistically analysed by means of SAS for personal computers (SAS/STAT Guide for Personal Computers, 1987). The frequency of pain relief (no supplementary analgesia needed) and adverse reactions in the 2 groups were compared by Fisher’s exact test (2sided) in the FREQ procedure. Within treatment groups, the centres were compared by the 2-sided exact test, for tables with small sample sizes, in the FREQ procedure. Age, weight and relative pain intensity were compared by Wilcoxon’s 2-sample test (2-sided) with respect to treatment groups, and by KruskalWallis’s test with respect to the centres within treatment groups. The efficacy of each treatment was tested by a Wilcoxon I-sample test (null
hypothesis: median relative pain score = 100%) within treatments at 10, 20 and 30 min after each treatment. Results After treatment, 17/63 patients in the enema group (27%) needed supplementary analgesia before or 30 min after treatment compared with 5/53 in the intravenous group (9%) (P=0.018). The difference between centres within treatment groups was not statistically significant. The analgesic effect of the 2 treatments was assessed in terms of relative pain intensity, i.e. pain intensity as a percentage of initial pain intensity. The mean relative pain intensity as a function of time since treatment is shown in the Figure. Relative pain relief was significantly better in both groups 10,20 and 30 rnin after administration than before treatment (all 6 P values
0007- I33 1/90/0065 4576/%1000
8 1990 British Journal of Urology
Treatment of Ureteric Colic. Intravenous versus Rectal Administration of Indomethacin I. NISSEN, H. BIRKE, J. B. OLSEN, E. WURTZ,K. LORENTZEN, H. SALOMON, P. LYNGE,P. FLY, T. H. J0RGENSEN. S. SVANE and B. B. NIELSEN Departments of Surgery, Thisted, Esbjerg, Kolding, Holstedbro, Holbaek, Skive, Nykobing Mors, Ssnderborg and Viborg Hospitals; Department of Urology, Gentofte Hospital, Gentofte. Denmark
Summary-A randomised multicentre clinical trial was undertaken to compare the effect on pain of indomethacin administered either intravenously or rectally to 1 16 patients with ureteric colic. Adverse reactions were also assessed. Of the patients receiving the intravenous injection, 4 8 / 5 3 (91%) achieved good pain relief ( i e . no supplementary analgesia was required) 30 min after administration, compared with 4 6 / 6 3 (73%) receiving the enema. Significantly more side effects occurred in the group treated intravenously. It was concluded that indomethacin administered as an enema was less effective than the intravenous form, but it should be regarded as a good alternative in the treatment of ureteric colic.
The pain caused by the passage of a ureteric stone results from increased pelviureteric pressure (Risholm 1954; Kiil, 1957) which produces increased tension in the pelvic and ureteric wall (Holmlund and Svanvik, 1982). Potent inhibitors of prostaglandin synthesis such as indomethacin (Holmlund and Sjodin, 1978) and diclofenac (Lundstam et al., 1982) relieve renal colic effectively when given parenterally. Parenteral administration, however, has the disadvantage of requiring either admission to hospital or the presence of medical staff before pain relief can be achieved. Oral medication is not suitable because of the nausea and vomiting that often accompany acute ureteric colic. A better alternative would seem to be rectal administration, which has none of these disadvantages. Bioavailability studies (Jensen, 1985)have shown comparability between indomethacin 100 mg given as a rectal solution and 50 mg given intravenously. Using these dosages and routes of administration, we assessed indomethacin in terms of efficacy and safety in the treatment of ureteric colic. Accepted for publication 1 I October 1989
Patients and Methods
The inclusion criteria for this multicentre, doubleblind, randomised trial were clinical symptoms of ureteric colic, age range 18 to 75 years, and informed consent. Exclusion criteria are listed in Table 1. Safety was assessed in all patients receiving treatment. The efficacyof the drug was analysed statistically only when the diagnosis had been confirmed either by intravenous urography or by spontaneous passage of the stone. Of the 423 patients registered, 265 were excluded for 1 or more of the reasons listed in Table 1 . There was no statistically significant difference in age, sex and weight of these 265 patients and the 158 who were included in the study. The diagnosis could not be verified in 42/ 158 patients and so the statistical analysis was based on 116 patients; 53 of these received indomethacin intravenously and 63 received it as an enema. There was no statistically significant difference between the 2 groups with respect to age, sex, weight or pretreatment pain score. The medication was prepared shortly before administration. The enema was always given first and the injection (over 5 min) began immediately afterwards.
576
577
URETERIC COLIC AND ADMINISTRATION OF INDOMETHACIN
Table 1 Reasons for Exclusion of 265 patients Reoson
Morphine treatment within 4 h NSAID treatment within 24 h Informed consent not given N o clinical symptoms Age below 18 or above 75 years Peptic ulcer or gastritis Severe heart/lung/kidney disease Analgesia unnecessary NSAID allergy Known or suspected pregnancy Staff pressed for time Already in the study Haemorrhagic diathesis Medication lost Intense pain Recent surgery Malignant hypertension Not known
No. of patients I02 69 48 22 22 19 15 14 10
4 3 2 1 1 I 1 0 I
oj264
39 26 18 8
8 7 6 5 4 2 I 0.8 0.4 0.4 0.4 0.4 0 0.4
Some patients had more than 1 reason for exclusion and not all patients were assessed with regard to all possible reasons.
The intensity of pain was assessed before and 10, 20 and 30min after administration by a visual analogue scale (VAS, 100 mm). Patients were asked at 30min whether or not the pain relief was satisfactory; if not, they were given the analgesic commonly used at that particular hospital. All answers were recorded. Adverse effects were registered on a special form at the time of treatment and a note was made as to whether the complaint was reported spontaneously or elicited by general questioning. Patients were not allowed to drink liquids while the pain persisted. Statistical methods The data were statistically analysed by means of SAS for personal computers (SAS/STAT Guide for Personal Computers, 1987). The frequency of pain relief (no supplementary analgesia needed) and adverse reactions in the 2 groups were compared by Fisher’s exact test (2sided) in the FREQ procedure. Within treatment groups, the centres were compared by the 2-sided exact test, for tables with small sample sizes, in the FREQ procedure. Age, weight and relative pain intensity were compared by Wilcoxon’s 2-sample test (2-sided) with respect to treatment groups, and by KruskalWallis’s test with respect to the centres within treatment groups. The efficacy of each treatment was tested by a Wilcoxon I-sample test (null
hypothesis: median relative pain score = 100%) within treatments at 10, 20 and 30 min after each treatment. Results After treatment, 17/63 patients in the enema group (27%) needed supplementary analgesia before or 30 min after treatment compared with 5/53 in the intravenous group (9%) (P=0.018). The difference between centres within treatment groups was not statistically significant. The analgesic effect of the 2 treatments was assessed in terms of relative pain intensity, i.e. pain intensity as a percentage of initial pain intensity. The mean relative pain intensity as a function of time since treatment is shown in the Figure. Relative pain relief was significantly better in both groups 10,20 and 30 rnin after administration than before treatment (all 6 P values
