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Nifedipine for the relief of renal colic: A double-blind, placebo-controlled clinical trial
ORIGINAL CONTRIBUTION nifedipine, renal colic
Nifedipine for the Relief of Renal Colic: A Double.Blind, Clinical Trial Pain from ureteral stones is believed to be due to spasm and hyperperistalsis of the involved ureter. Nifedipine has been shown to decrease human ureteral spasm in vitro. Conflicting results have been reported concerning the clinical efficacy of nifedipine in relieving acute renal colic. This prospective, double-blind, crossover clinical trial evaluated the acute pain relief obtained in 30 patients who had ureteral stones. All patients had ureteral stones documented either by plain abdominal radiograph (six), intravenous pyelogram (I6), or passage of the stone(s) in the urine (eight). Each patient served as his own control. The mean pain relief scores for placebo versus 10 to 20 mg oral nifedipine were O.7 +- 1.8 and 1.2 +_ 2.5, respectively, as measured on a visual analogue scale (P = .404). Seven patients received clinically significant relief associated with nifedipine, and three patients received relief from placebo (P = .300). Twenty patients (66%) did not experience clinically significant relief from either treatment. We conclude that nifedipine does not differ significantly from placebo in providing relief from acute renal colic. [Caravati EM, Runge JW, Bossart PJ, Martinez JC, HartseI1 SC, Williamson SG: Nifedipine for the relief of renal colic: A double-blind, placebo-controlled clinical trial. Ann Emerg Med April I989;I8:352-354.]
INTRODUCTION Renal colic is an acutely painful condition that often requires large doses of parenteral narcotics for relief. The pain is attributed to spasm and hyperperistalsis of the involved ureterJ Calcium channel blockers, such as nifedipine, have been shown to dilate spastic coronary arteries z and to have a relaxing effect in vitro on guinea pig and h u m a n ureteral spasm. 3,4 Patients with acute renal colic have been reported to receive pain relief associated with administration of oral nifedipine, s-7 Our study was designed to determine if oral nifedipine differs from placebo in relieving acute pain secondary to nephrolithiasis.
E Martin Caravati, MD, FACEP* Jeffery W Runge, MD, FACEPt Philip J Bossart, MD* J Chris Martinez, MDt Stephen C Hartsell, MD* Steven G Williamson, MDt Salt Lake City, Utah Charlotte, North Carolina From the Division of Emergency Medicine, University of Utah School of Medicine, Salt Lake City, Utah,* and The Department of Emergency Medicine, Charlotte Memorial Hospital and Medical Center, Charlotte, North Carolina.t Received for publication October 17, 1988. Accepted for publication December 12, 1988. This study was supported by a grant from Pfizer Pharmaceuticals, New York, New York. Address for reprints: E Martin Caravati, MD, Emergency Department, University Hospital, 50 N Medical Drive, Salt Lake City, Utah 84132.
METHODS Our study was conducted simultaneously at two teaching hospitals. The University of Utah Hospital is a 375-bed university hospital with approximately 18,000 emergency department patient visits annually. Charlotte Memorial Hospital and Medical Center is an 820-bed community-based hospital with 85,000 ED patient visits annually. All patients between 18 and 75 years of age presenting to the ED with the signs and symptoms of acute renal colic were eligible for inclusion in the study. Patients were excluded for k n o w n hypersensitivity to nifedipine, concurrent calcium channel blocker therapy, unstable vital signs (heart rate more than 150 or systolic blood pressure less than 100 m m Hg), severe aortic stenosis, pregnancy, myocardial infarction within one m o n t h before entry, coronary artery bypass surgery within three m o n t h s before entry, systolic blood pressure more than 170 m m Hg, diastolic blood pressure more than 110 m m Hg, or the use of any investigational drug within a one-month period before entry into the study. The presence of nephrolithiasis was documented immediately after the study treatment by intravenous pyelogram, plain abdominal radiograph, or passage of the stone in the urine. Patients in w h o m nephrolithiasis could not be documented were excluded from data analysis.
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NIFEDIPINE Caravati et al
The study was conducted as a prospective, randomized, double-blind, crossover, placebo-controlled clinical trial. Written informed consent was obtained from the patient before enrollment in the study. The patients were randomized by random n u m b e r table to one of two possible treatm e n t sequences. The treatment sequence was either administration of one or two 10-rag nifedipine capsules, followed by crossover placebo capsules, or vice versa. Each p a t i e n t served as his o w n control. The nifedipine and placebo capsules were identical in appearance. The investigator and p a t i e n t were blinded as to which sequence the patient was assigned. Patients were asked to assess their pain severity immediately before and 15 m i n u t e s after a d m i n i s t r a t i o n of the first capsule (phase 1). Because peak effects of nifedipine are noted in 20 minutes, we believed that 15 minutes was enough time to allow some response to t r e a t m e n t . We did n o t want patients to remain in pain for an u n d u e period and c h o s e a 30m i n u t e limit, thereby allowing two 15-minute treatment intervals before discontinuing the study. Patients assessed pain severity on an unmarked 10-cm horizontal visual analogue scale with vertical stops at each end. 8 T h e d e s c r i p t i o n s " n o pain" and "worst possible pain" were at the ends b e y o n d the stops. The scale was explained carefully to all patients, w h o were allowed to see their previous marks for comparison. Each was instructed to bite the capsule, express the contents, and then swallow it. If the patient experienced little or no pain relief 15 minutes after administration of the first capsule, he was then administered the crossover capsule, and pain assessm e n t s were r e p e a t e d in a s i m i l a r fashion (phase 2). If significant pain relief occurred by the first 15-minute assessment mark, the p a t i e n t was not crossed over but reassessed again in another 15 minutes for pain severity. If pain relief continued, the patient was given a second dose of the same capsule and not crossed over to phase 2, and pain severity was reassessed again in 15 minutes. Any patient with complete or nearly complete pain relief in phase 1 was not crossed over into phase 2. If m o r e than one p o s t - t r e a t m e n t pain severity score was recorded, the 42/353
last recorded score was used to calculate mean pain severity score. The relief score was calculated by subtracting the post-treatment from the baseline pain severity score. If the patient r e c e i v e d i n s i g n i f i c a n t p a i n relief from both phases, the study was discontinued and the patient was given n a r c o t i c analgesia as needed. T h e m a x i m u m n u m b e r of capsules that could be administered was two per phase. The m a x i m u m length of time a patient would go without pain relief during the study was 30 minutes. " C l i n i c a l l y s i g n i f i c a n t " pain relief was defined as enough relief to subsequently alter pain management (ie, no narcotics). Vital signs were o b t a i n e d at 15m i n u t e i n t e r v a l s t h r o u g h o u t the study. All p a t i e n t s s t r a i n e d their urine for stones. No other treatment (eg, fluid diuresis) was given during the study. T h e p a t i e n t s w h o had n e p h r o g r a m s p e r f o r m e d had t h e m d o n e i m m e d i a t e l y after the s t u d y period. All o b s e r v e d and p a t i e n t reported side effects were recorded by the investigator. The study was approved by the h u m a n investigational review boards at both hospitals. Statistical analysis was performed with the Wilcoxon signed rank test for comparing means of nonparamettic paired samples and Fisher's exact test for proportions. All statistical tests were two tailed. Values are expressed as mean +_ SD. P < .05 was considered statistically significant.
RESULTS Thirty-five patients were enrolled in the study. Five were e x c l u d e d from analysis, and two v o l u n t a r i l y w i t h d r e w f r o m the study early in phase 1 because of pain and did not complete the pain score analysis. The diagnosis of nephrolithiasis could not be d o c u m e n t e d in three other patients. Therefore, 30 patients were available for analysis. T h e average age was 37 -+ 12 years; 27 were m e n and three were women. N e p h r o l i t h i a s i s was d o c u m e n t e d by intravenous pyelogram in 16 patients, plain abdominal radiograph in six, and passage of the stone(s) in eight. All 30 p a t i e n t s had m i c r o scopic hematuria (more than 5 RBC/ high power field of urinary sediment) on urinalysis. There were no concurrent u r i n a r y tract infections. Thirteen patients received oral nifedipine in phase 1, and nine of t h e m were Annals of Emergency Medicine
crossed over to placebo in phase 2. Four of the patients receiving nifedipine in phase 1 had significant or complete pain relief and were not eligible for the crossover phase. Seventeen p a t i e n t s received p l a c e b o in phase 1, and all were crossed over to nifedipine in phase 2. Therefore, a total of 30 patients received nifedipine, and 26 of them also received placebo during the study. T h e m e a n p r e p l a c e b o and prenifedipine pain severity scores were 7.2 + 1.8 and 7.0 + 2.3, respectively (P = .50). The mean post-placebo and post-nifedipine pain severity scores were 6.5 +- 2.7 and 5.7 + 3.2, respectively (P = .496). The m e a n relief scores associated with placebo and nifedipine were 0.7 -+ 1.8 and 1.2 +_ 2.5, respectively (P = .404). Twenty of the 26 patients (77%) receiving both nifedipine and placebo did not experience "clinically significant" pain relief from either treatm e n t and subsequently required narcotic analgesia to feel comfortable. Seven of the 30 patients (23%) receiving nifedipine experienced "clinically s i g n i f i c a n t " pain relief, and three of 26 patients (12%) experienced relief with placebo (P = .31). These patients did not require narcotics for pain. Patients demonstrating "clinically significant" relief reported at least a 45% reduction in pain severity or a 3.0-cm difference on the analogue pain severity scale. Three patients experienced transient side effects in association with nifedipine. There was one episode each of facial flushing, fatigue, and vomiting. No adverse reactions were n o t e d in association w i t h placebo. The only significant difference in the change of vital signs between groups was after the second dose of the initial t r e a t m e n t (phase 1). T h o s e patients on nifedipine had a 4.3 m m Hg drop in systolic blood pressure, while those on placebo had an increase of 10.7 m m Hg (P = .02).
DISCUSSION S m o o t h m u s c l e c o n t r a c t i o n is t h o u g h t to be r e l a t e d to c a l c i u m ionic flux and its activation of contractile proteins. 9 Nifedipine, a potent c a l c i u m c h a n n e l blocker, has been shown to inhibit smooth muscle contraction in the rat uterus, 10 guinea pig ureter, 3 h u m a n esophagus, ureter, peripheral vasculature, and coronary arteries.2,4,11 18:4 April 1989
The severe p a i n associated w i t h ureteral stones is believed to be partially due to s p a s m a n d h y p e r peristalsis of s m o o t h m u s c l e i n the ureter, renal pelvis, and calyx. 1 This pain often requires large doses of parenteral narcotics for adequate relief. In 1985, Carrol s reported rapid relief of uretera] c o l i c i n t w o p a t i e n t s treated w i t h 10 to 20 mg oral nifedipine. B o r t o l o t t i a n d associates 6 compared 40 m g IV s c o p o l a m i n e butylbromide w i t h 20 rng sublingual nifedipine in the t r e a t m e n t of 16 patients w i t h b i l i a r y and 16 p a t i e n t s with renal colic. They found that nifedipine was e f f e c t i v e i n r e l i e v i n g pain a n d m o r e e f f i c a c i o u s t h a n scopolamine. Significant p a i n relief was noted 15 m i n u t e s after the adm i n i s t r a t i o n of n i f e d i p i n e . T h e i r study was not blinded, however, and stones were n o t found in 25% and 56% of patients with biliary or renal colic, respectively. Lloret and a s s o c i a t e s 7 a d m i n i s tered 10 mg n i f e d i p i n e s u b l i n g u a l l y to 25 patients w i t h renal colic and noted the "disappearance of pain" in 44%. However, d o c u m e n t a t i o n of nephrolithiasis was reported in only 10% of the patients. Other studies have reported failure of nifedipine to relieve renal colic, but the investigators and patients were n o t b l i n d e d with regard to t r e a t m e n t , a n d the sample sizes were very small in these protocols.lZ, 13 Blinding is an important factor in obtaining accurate results from pain studies. 1~ Our study used a prospective, randomized, placebo-controlled protocol in which both the patient and investigator were blinded to the t r e a t m e n t sequence. Each patient served as his own control. All patients had documented u r e t e r a l s t o n e s a s s o c i a t e d with their pain. We found no significant difference i n the m e a n baseline, post-treatment, or pain relief scores between the placebo and 10 to 20 mg oral nifedipine groups (P > .4). Seven of 30 patients (23%) reported "clinically s i g n i f i c a n t " relief f r o m nifedipine, while three of 26 (12%) reported relief with placebo (P ~- .31). "Clinically significant" pain relief in our study required at least a reduction in pain of 3.0 cm on the visual
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a n a l o g u e scale from b a s e l i n e . T h i s study has a power of 90% to detect a difference of 3.0 cm of pain measurem e n t between the nifedipine and placebo t r e a t m e n t groups w i t h 26 and 30 p a t i e n t s i n each group, respectively. T h e p r o b a b i l i t y of failing to demonstrate this difference between the two t r e a t m e n t groups w h e n one actually exists is termed "beta." The beta error in our study was 10%. 15 O n e l i m i t a t i o n of our study was t h a t it was d i f f i c u l t to d e t e r m i n e whether there were any residual effects from n i f e d i p i n e a d m i n i s t e r e d during phase 1 on phase 2 placebo pain scores. We believed that an extended " w a s h o u t " phase was not fair to patients in extreme pain. Two of the three p a t i e n t s receiving "clinically significant" relief from placebo had received n i f e d i p i n e i n the previous phase. One patient reported relief 30 m i n u t e s after r e c e i v i n g the placebo capsule, w h i c h was 60 minutes after he had received the phase 1 nifedipine capsule. Because the clinical effects of oral nifedipine peak w i t h i n 20 m i n u t e s of ingestion, z we believe that it is unlikely that this p a t i e n t ' s relief was associated with nifedipine. The other patient reported relief 15 m i n u t e s after placebo, w h i c h was 30 m i n u t e s after p h a s e 1 n i f e d i p i n e . T h i s pat i e n t ' s p a i n relief could have b e e n secondary to the phase 1 n i f e d i p i n e even t h o u g h he reported relief after phase 2 placebo. If pain relief is att r i b u t e d to n i f e d i p i n e in the l a t t e r case, then eight patients (27%) would have received relief from n i f e d i p i n e and two from placebo (8%) {P = .06). Another l i m i t a t i o n was that the pain of renal colic tends to fluctuate over time and such changes i n pain intensity may be interpreted as drug effect. Our study suggests that nifedipine is no different from placebo in the relief of renal colic. There are several possible explanations for this observation. It may be that nifedipine does n o t relieve ureteral spasm i n v i v o ; that 10 to 20 mg given over 15 to 30 m i n u t e s is not an adequate dose; or that another m e c h a n i s m , such as increased renal capsular pressure from ureteral obstruction, is primarily responsible for the pain.
Annals of Emergency Medicine
CONCLUSION Nifedipine has been found to have a relaxing effect on ureteral smooth m u s c l e spasm i n v i t r o . C o n f l i c t i n g observations as to its clinical efficacy i n r e l i e v i n g a c u t e r e n a l colic have been reported previously. This prospective, double-blind, crossover c l i n i c a l t r i a l of 30 p a t i e n t s w i t h acute renal colic d e m o n s t r a t e d that nifedipine, 10 to 20 mg orally, was no different from placebo in the relief of pain associated with ureteral stones.
REFERENCES 1. Abber JC, McAninch: Renal colic: Emergency evaluationand management.Am J Emerg Med 1985;3:56-63. 2. Vanhoutte PM, Cohen RA: Calcium-entry blockers and cardiovascular disease. Am ] Cardiol 1983;52:99ad03a. 3. Maggi CA, Meli A: The effect of nifedipine and verapamil on KCl-inducedrhythmic contractions of guinea pig ureter in vitro. Experientia 1984;40:681-686. 4. Hertle L: Pharmacologicalstudy on the motility of isolated preparations of the human up- ' per urinary tract. Arch Phormacoi 1982;319 (suppl):R33. 5. Carrol W: Nifedipineand ureteral colic (letter). Ann Intern Med 1985;102:864. 6. Bortolotti M, Trisolina G, Barbara L: Nifedipine in biliary and renal colic (letter). JAMA 1987;258:3516. 7. Lloret J, Vila A, Puig X, et al: Nifedipinein the treatment of renal colic. Methods Find Exp C]in Pharmacol 1986;8:575-579. 8. Huskisson EC: Visual analogue scales, in Melzack R {ed): Pain Measurement and Assessment. New York, Raven Press, 1983, p 33-37. 9. Hurwitz L, McGuffeeLJ: Calcium in smooth muscle function, in Weiss GB (ed): CalcJunl in Drug Action. New York, Raven Press, 1978, p 75-93. 10. Varagic VM, MilovanovicSR, Srkalovic G: The effects of calcium-channelblockingagents on the various types of smooth muscle activation of the isolated rat uterus. Arch Int Pharmacodyn 1984;270:79-87. 11. Hongo M, Traube M, McAllisterRG, et ah Effects of nifedipineon esophageal motor function in humans: Correlation with plasma nifedipine concentration. Gastroenterology 1984; 86:8-12.
12. Coppens L, Lustman F: Nifedipine and ureteral colic (letter]. Ann Intern Med 19861 105:967. 13. McCormick M, Williot P, LaPointe S, et ah Nifedipine and ureteral colic (letter). Ann Intern Med 1986;104:590. 14. Dundee JW: Clinical evaluationof mild analgesics. Br J Clin PharmacoI 1980;10:329s-334s. 15. Brown CG, KelenGD, Ashton JJ, et al: The beta error and sample size determination in clinical trials in emergency medicine. Ann Emerg Med 1987;16:183-187.
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Nifedipine for the Relief of Renal Colic: A Double.Blind, Clinical Trial Pain from ureteral stones is believed to be due to spasm and hyperperistalsis of the involved ureter. Nifedipine has been shown to decrease human ureteral spasm in vitro. Conflicting results have been reported concerning the clinical efficacy of nifedipine in relieving acute renal colic. This prospective, double-blind, crossover clinical trial evaluated the acute pain relief obtained in 30 patients who had ureteral stones. All patients had ureteral stones documented either by plain abdominal radiograph (six), intravenous pyelogram (I6), or passage of the stone(s) in the urine (eight). Each patient served as his own control. The mean pain relief scores for placebo versus 10 to 20 mg oral nifedipine were O.7 +- 1.8 and 1.2 +_ 2.5, respectively, as measured on a visual analogue scale (P = .404). Seven patients received clinically significant relief associated with nifedipine, and three patients received relief from placebo (P = .300). Twenty patients (66%) did not experience clinically significant relief from either treatment. We conclude that nifedipine does not differ significantly from placebo in providing relief from acute renal colic. [Caravati EM, Runge JW, Bossart PJ, Martinez JC, HartseI1 SC, Williamson SG: Nifedipine for the relief of renal colic: A double-blind, placebo-controlled clinical trial. Ann Emerg Med April I989;I8:352-354.]
INTRODUCTION Renal colic is an acutely painful condition that often requires large doses of parenteral narcotics for relief. The pain is attributed to spasm and hyperperistalsis of the involved ureterJ Calcium channel blockers, such as nifedipine, have been shown to dilate spastic coronary arteries z and to have a relaxing effect in vitro on guinea pig and h u m a n ureteral spasm. 3,4 Patients with acute renal colic have been reported to receive pain relief associated with administration of oral nifedipine, s-7 Our study was designed to determine if oral nifedipine differs from placebo in relieving acute pain secondary to nephrolithiasis.
E Martin Caravati, MD, FACEP* Jeffery W Runge, MD, FACEPt Philip J Bossart, MD* J Chris Martinez, MDt Stephen C Hartsell, MD* Steven G Williamson, MDt Salt Lake City, Utah Charlotte, North Carolina From the Division of Emergency Medicine, University of Utah School of Medicine, Salt Lake City, Utah,* and The Department of Emergency Medicine, Charlotte Memorial Hospital and Medical Center, Charlotte, North Carolina.t Received for publication October 17, 1988. Accepted for publication December 12, 1988. This study was supported by a grant from Pfizer Pharmaceuticals, New York, New York. Address for reprints: E Martin Caravati, MD, Emergency Department, University Hospital, 50 N Medical Drive, Salt Lake City, Utah 84132.
METHODS Our study was conducted simultaneously at two teaching hospitals. The University of Utah Hospital is a 375-bed university hospital with approximately 18,000 emergency department patient visits annually. Charlotte Memorial Hospital and Medical Center is an 820-bed community-based hospital with 85,000 ED patient visits annually. All patients between 18 and 75 years of age presenting to the ED with the signs and symptoms of acute renal colic were eligible for inclusion in the study. Patients were excluded for k n o w n hypersensitivity to nifedipine, concurrent calcium channel blocker therapy, unstable vital signs (heart rate more than 150 or systolic blood pressure less than 100 m m Hg), severe aortic stenosis, pregnancy, myocardial infarction within one m o n t h before entry, coronary artery bypass surgery within three m o n t h s before entry, systolic blood pressure more than 170 m m Hg, diastolic blood pressure more than 110 m m Hg, or the use of any investigational drug within a one-month period before entry into the study. The presence of nephrolithiasis was documented immediately after the study treatment by intravenous pyelogram, plain abdominal radiograph, or passage of the stone in the urine. Patients in w h o m nephrolithiasis could not be documented were excluded from data analysis.
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NIFEDIPINE Caravati et al
The study was conducted as a prospective, randomized, double-blind, crossover, placebo-controlled clinical trial. Written informed consent was obtained from the patient before enrollment in the study. The patients were randomized by random n u m b e r table to one of two possible treatm e n t sequences. The treatment sequence was either administration of one or two 10-rag nifedipine capsules, followed by crossover placebo capsules, or vice versa. Each p a t i e n t served as his o w n control. The nifedipine and placebo capsules were identical in appearance. The investigator and p a t i e n t were blinded as to which sequence the patient was assigned. Patients were asked to assess their pain severity immediately before and 15 m i n u t e s after a d m i n i s t r a t i o n of the first capsule (phase 1). Because peak effects of nifedipine are noted in 20 minutes, we believed that 15 minutes was enough time to allow some response to t r e a t m e n t . We did n o t want patients to remain in pain for an u n d u e period and c h o s e a 30m i n u t e limit, thereby allowing two 15-minute treatment intervals before discontinuing the study. Patients assessed pain severity on an unmarked 10-cm horizontal visual analogue scale with vertical stops at each end. 8 T h e d e s c r i p t i o n s " n o pain" and "worst possible pain" were at the ends b e y o n d the stops. The scale was explained carefully to all patients, w h o were allowed to see their previous marks for comparison. Each was instructed to bite the capsule, express the contents, and then swallow it. If the patient experienced little or no pain relief 15 minutes after administration of the first capsule, he was then administered the crossover capsule, and pain assessm e n t s were r e p e a t e d in a s i m i l a r fashion (phase 2). If significant pain relief occurred by the first 15-minute assessment mark, the p a t i e n t was not crossed over but reassessed again in another 15 minutes for pain severity. If pain relief continued, the patient was given a second dose of the same capsule and not crossed over to phase 2, and pain severity was reassessed again in 15 minutes. Any patient with complete or nearly complete pain relief in phase 1 was not crossed over into phase 2. If m o r e than one p o s t - t r e a t m e n t pain severity score was recorded, the 42/353
last recorded score was used to calculate mean pain severity score. The relief score was calculated by subtracting the post-treatment from the baseline pain severity score. If the patient r e c e i v e d i n s i g n i f i c a n t p a i n relief from both phases, the study was discontinued and the patient was given n a r c o t i c analgesia as needed. T h e m a x i m u m n u m b e r of capsules that could be administered was two per phase. The m a x i m u m length of time a patient would go without pain relief during the study was 30 minutes. " C l i n i c a l l y s i g n i f i c a n t " pain relief was defined as enough relief to subsequently alter pain management (ie, no narcotics). Vital signs were o b t a i n e d at 15m i n u t e i n t e r v a l s t h r o u g h o u t the study. All p a t i e n t s s t r a i n e d their urine for stones. No other treatment (eg, fluid diuresis) was given during the study. T h e p a t i e n t s w h o had n e p h r o g r a m s p e r f o r m e d had t h e m d o n e i m m e d i a t e l y after the s t u d y period. All o b s e r v e d and p a t i e n t reported side effects were recorded by the investigator. The study was approved by the h u m a n investigational review boards at both hospitals. Statistical analysis was performed with the Wilcoxon signed rank test for comparing means of nonparamettic paired samples and Fisher's exact test for proportions. All statistical tests were two tailed. Values are expressed as mean +_ SD. P < .05 was considered statistically significant.
RESULTS Thirty-five patients were enrolled in the study. Five were e x c l u d e d from analysis, and two v o l u n t a r i l y w i t h d r e w f r o m the study early in phase 1 because of pain and did not complete the pain score analysis. The diagnosis of nephrolithiasis could not be d o c u m e n t e d in three other patients. Therefore, 30 patients were available for analysis. T h e average age was 37 -+ 12 years; 27 were m e n and three were women. N e p h r o l i t h i a s i s was d o c u m e n t e d by intravenous pyelogram in 16 patients, plain abdominal radiograph in six, and passage of the stone(s) in eight. All 30 p a t i e n t s had m i c r o scopic hematuria (more than 5 RBC/ high power field of urinary sediment) on urinalysis. There were no concurrent u r i n a r y tract infections. Thirteen patients received oral nifedipine in phase 1, and nine of t h e m were Annals of Emergency Medicine
crossed over to placebo in phase 2. Four of the patients receiving nifedipine in phase 1 had significant or complete pain relief and were not eligible for the crossover phase. Seventeen p a t i e n t s received p l a c e b o in phase 1, and all were crossed over to nifedipine in phase 2. Therefore, a total of 30 patients received nifedipine, and 26 of them also received placebo during the study. T h e m e a n p r e p l a c e b o and prenifedipine pain severity scores were 7.2 + 1.8 and 7.0 + 2.3, respectively (P = .50). The mean post-placebo and post-nifedipine pain severity scores were 6.5 +- 2.7 and 5.7 + 3.2, respectively (P = .496). The m e a n relief scores associated with placebo and nifedipine were 0.7 -+ 1.8 and 1.2 +_ 2.5, respectively (P = .404). Twenty of the 26 patients (77%) receiving both nifedipine and placebo did not experience "clinically significant" pain relief from either treatm e n t and subsequently required narcotic analgesia to feel comfortable. Seven of the 30 patients (23%) receiving nifedipine experienced "clinically s i g n i f i c a n t " pain relief, and three of 26 patients (12%) experienced relief with placebo (P = .31). These patients did not require narcotics for pain. Patients demonstrating "clinically significant" relief reported at least a 45% reduction in pain severity or a 3.0-cm difference on the analogue pain severity scale. Three patients experienced transient side effects in association with nifedipine. There was one episode each of facial flushing, fatigue, and vomiting. No adverse reactions were n o t e d in association w i t h placebo. The only significant difference in the change of vital signs between groups was after the second dose of the initial t r e a t m e n t (phase 1). T h o s e patients on nifedipine had a 4.3 m m Hg drop in systolic blood pressure, while those on placebo had an increase of 10.7 m m Hg (P = .02).
DISCUSSION S m o o t h m u s c l e c o n t r a c t i o n is t h o u g h t to be r e l a t e d to c a l c i u m ionic flux and its activation of contractile proteins. 9 Nifedipine, a potent c a l c i u m c h a n n e l blocker, has been shown to inhibit smooth muscle contraction in the rat uterus, 10 guinea pig ureter, 3 h u m a n esophagus, ureter, peripheral vasculature, and coronary arteries.2,4,11 18:4 April 1989
The severe p a i n associated w i t h ureteral stones is believed to be partially due to s p a s m a n d h y p e r peristalsis of s m o o t h m u s c l e i n the ureter, renal pelvis, and calyx. 1 This pain often requires large doses of parenteral narcotics for adequate relief. In 1985, Carrol s reported rapid relief of uretera] c o l i c i n t w o p a t i e n t s treated w i t h 10 to 20 mg oral nifedipine. B o r t o l o t t i a n d associates 6 compared 40 m g IV s c o p o l a m i n e butylbromide w i t h 20 rng sublingual nifedipine in the t r e a t m e n t of 16 patients w i t h b i l i a r y and 16 p a t i e n t s with renal colic. They found that nifedipine was e f f e c t i v e i n r e l i e v i n g pain a n d m o r e e f f i c a c i o u s t h a n scopolamine. Significant p a i n relief was noted 15 m i n u t e s after the adm i n i s t r a t i o n of n i f e d i p i n e . T h e i r study was not blinded, however, and stones were n o t found in 25% and 56% of patients with biliary or renal colic, respectively. Lloret and a s s o c i a t e s 7 a d m i n i s tered 10 mg n i f e d i p i n e s u b l i n g u a l l y to 25 patients w i t h renal colic and noted the "disappearance of pain" in 44%. However, d o c u m e n t a t i o n of nephrolithiasis was reported in only 10% of the patients. Other studies have reported failure of nifedipine to relieve renal colic, but the investigators and patients were n o t b l i n d e d with regard to t r e a t m e n t , a n d the sample sizes were very small in these protocols.lZ, 13 Blinding is an important factor in obtaining accurate results from pain studies. 1~ Our study used a prospective, randomized, placebo-controlled protocol in which both the patient and investigator were blinded to the t r e a t m e n t sequence. Each patient served as his own control. All patients had documented u r e t e r a l s t o n e s a s s o c i a t e d with their pain. We found no significant difference i n the m e a n baseline, post-treatment, or pain relief scores between the placebo and 10 to 20 mg oral nifedipine groups (P > .4). Seven of 30 patients (23%) reported "clinically s i g n i f i c a n t " relief f r o m nifedipine, while three of 26 (12%) reported relief with placebo (P ~- .31). "Clinically significant" pain relief in our study required at least a reduction in pain of 3.0 cm on the visual
18:4 April 1989
a n a l o g u e scale from b a s e l i n e . T h i s study has a power of 90% to detect a difference of 3.0 cm of pain measurem e n t between the nifedipine and placebo t r e a t m e n t groups w i t h 26 and 30 p a t i e n t s i n each group, respectively. T h e p r o b a b i l i t y of failing to demonstrate this difference between the two t r e a t m e n t groups w h e n one actually exists is termed "beta." The beta error in our study was 10%. 15 O n e l i m i t a t i o n of our study was t h a t it was d i f f i c u l t to d e t e r m i n e whether there were any residual effects from n i f e d i p i n e a d m i n i s t e r e d during phase 1 on phase 2 placebo pain scores. We believed that an extended " w a s h o u t " phase was not fair to patients in extreme pain. Two of the three p a t i e n t s receiving "clinically significant" relief from placebo had received n i f e d i p i n e i n the previous phase. One patient reported relief 30 m i n u t e s after r e c e i v i n g the placebo capsule, w h i c h was 60 minutes after he had received the phase 1 nifedipine capsule. Because the clinical effects of oral nifedipine peak w i t h i n 20 m i n u t e s of ingestion, z we believe that it is unlikely that this p a t i e n t ' s relief was associated with nifedipine. The other patient reported relief 15 m i n u t e s after placebo, w h i c h was 30 m i n u t e s after p h a s e 1 n i f e d i p i n e . T h i s pat i e n t ' s p a i n relief could have b e e n secondary to the phase 1 n i f e d i p i n e even t h o u g h he reported relief after phase 2 placebo. If pain relief is att r i b u t e d to n i f e d i p i n e in the l a t t e r case, then eight patients (27%) would have received relief from n i f e d i p i n e and two from placebo (8%) {P = .06). Another l i m i t a t i o n was that the pain of renal colic tends to fluctuate over time and such changes i n pain intensity may be interpreted as drug effect. Our study suggests that nifedipine is no different from placebo in the relief of renal colic. There are several possible explanations for this observation. It may be that nifedipine does n o t relieve ureteral spasm i n v i v o ; that 10 to 20 mg given over 15 to 30 m i n u t e s is not an adequate dose; or that another m e c h a n i s m , such as increased renal capsular pressure from ureteral obstruction, is primarily responsible for the pain.
Annals of Emergency Medicine
CONCLUSION Nifedipine has been found to have a relaxing effect on ureteral smooth m u s c l e spasm i n v i t r o . C o n f l i c t i n g observations as to its clinical efficacy i n r e l i e v i n g a c u t e r e n a l colic have been reported previously. This prospective, double-blind, crossover c l i n i c a l t r i a l of 30 p a t i e n t s w i t h acute renal colic d e m o n s t r a t e d that nifedipine, 10 to 20 mg orally, was no different from placebo in the relief of pain associated with ureteral stones.
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12. Coppens L, Lustman F: Nifedipine and ureteral colic (letter]. Ann Intern Med 19861 105:967. 13. McCormick M, Williot P, LaPointe S, et ah Nifedipine and ureteral colic (letter). Ann Intern Med 1986;104:590. 14. Dundee JW: Clinical evaluationof mild analgesics. Br J Clin PharmacoI 1980;10:329s-334s. 15. Brown CG, KelenGD, Ashton JJ, et al: The beta error and sample size determination in clinical trials in emergency medicine. Ann Emerg Med 1987;16:183-187.
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