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Keywords:

  • Renal colic;
  • tenoxicam;
  • isosorbide dinitrate

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

Objective To determine the effectiveness of isosorbide dinitrate in combination with tenoxicam compared with tenoxicam alone for the relief of acute renal colic.

Patients and methods Fifty patients with acute renal colic were randomly and in a double blind fashion divided into two treatment groups of 25 each. Group 1 received tenoxicam (40 mg intravenously) and group 2 received tenoxicam (40 mg intravenously) plus sublingual isosorbide dinitrate (5 mg). The patients were compared for visual pain scores, heart rate and blood pressure between and within the groups before and after treatment.

Results Comparing the groups, group 2 had significantly lower pain scores after treatment (P < 0.05) but no other variables were significantly different (P > 0.05 for each). Within the groups the pain scores were significantly lower after treatment in both groups (P < 0.05). Group 2 also had a significantly lower heart rate and blood pressure after treatment (P < 0.05). There were no side-effects caused by tenoxicam and isosorbide dinitrate in either group.

Conclusion The use of tenoxicam alone or combined with isosorbide dinitrate was effective in relieving of renal colic, but the relief obtained with the combination was significantly greater than tenoxicam alone.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

Renal colic is one of the most common presentations of acute urinary obstruction; once diagnosed and all other surgical emergencies excluded, therapy must be started immediately to relieve the pain. There are various agents to treat renal colic but the standard treatment for severe renal colic has been the parenteral administration of narcotic analgesics. However, narcotics may exacerbate gastrointestinal symptoms and can cause excessive sedation [1]; fortunately, NSAIDs and non-narcotic analgesics are also available. In a meta-analysis of 19 studies, parenteral NSAIDs were shown to be as effective as narcotic analgesics [2].

Acute ureteric obstruction is a potent stimulus for renal PG synthesis, resulting in the sensitization of pain receptors [1]. Therefore, the drugs that inhibit PG synthesis, e.g. indomethacin and diclofenac sodium, are effective treatments for renal colic. Tenoxicam, a thiemothiazine derivative of the oxicam class, is also an inhibitor of PG synthesis and is also effective in treating acute renal colic [3,4]. When compared with pethidine, tenoxicam has a slower onset but provides the same pain relief after 30 min [4].

Structure-activity studies indicate that all thera-peutically active simple nitric and nitrous acid esters of polyalcohols, including isosorbide dinitrate, are capable of releasing nitric oxide (NO) in vascular smooth muscle tissues [5]. When NO interacts with guanyl cyclase, a haem protein and a target for NO, cGMP is increased and the smooth muscle relaxes. Nitrates can also cause relaxation of the smooth muscle of the genitourinary tract, but to date, because of their brief duration, this property has been of little clinical value [1,5].

In the present study, we determined whether it is possible to use the transient effect of isosorbide dinitrate on genitourinary smooth muscle to augment the established analgesic effect of tenoxicam in patients with severe renal colic.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

Fifty patients with renal colic presenting to the Department of Emergency Medicine were included in the study (40 men and 10 women). As exclusion criteria, the patients were questioned and examined for any contraindications to the use of isosorbide dinitrate and tenoxicam, e.g. drug allergy, presence of hypotension or suspicion of any surgical emergency. In addition, patients with active infection and renal colic associated with pyuria were excluded from the study to avoid any interfering factors such as infection-induced inflammatory reaction. Before the study, local ethical committee approval was obtained and all patients gave informed consent. To establish the diagnosis of urolithiasis, all the patients were questioned about the nature of their pain and underwent a physical examination, urine analysis, a radiological evaluation with direct abdominal X-rays and, where necessary, ultrasonography.

Just before starting treatment, the patient’s heart rate and BP were measured. A visual analogue pain scale was used to quantify the degree of pain, consisting of a 100 mm scale marked in 10 mm intervals, with the zero point designated ‘no pain’ and the 100 mm end as ‘the most intractable pain ever felt’. The patients were asked to mark the degree of pain using this analogue scoring system.

Two equal groups were formed randomly and in a double-blind fashion; group 1 was treated with intravenous tenoxicam (40 mg) and group 2 received intravenous tenoxicam (40 mg) plus sublingual isosorbide dinitrate (5 mg). The patients were re-evaluated for heart rate, BP and the pain score after 30 min. To record any adverse effects the patients were questioned about headache, evaluated for drug allergy, and any orthostatic hypotension assessed using BP measurements in those with symptoms such as dizziness or faintness when they stood upright.

The two groups were compared for age, pain scores, heart rate and BP before and after treatment using unpaired Student’s t-tests; the within-group differences for the same variables before and after treatment were assessed using paired Student’s t-tests.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

All the patients had intermittent flank pain as the primary complaint and physical examination showed costovertebral angle tenderness on the side of urolithiasis. There were no findings related to an acute abdomen, e.g. abdominal tenderness or rigidity. The body temperature of all the patients was within normal limits. The sites of the ureteric stones, as shown by radiological evaluations, are shown in Table 1. Urine analysis showed microscopic haematuria of varying degrees in all the patients, except for two in group 1 and one in group 2, who had normal findings; none of the patients had pyuria.

Table 1.  The site of the urinary stones, and the comparisons between and within the groups for the variables assessed before and after treatment
VariableGroup 1Group 2
  • *  

    P  < 0.05, between-group values;

  • †  

    P  < 0.05, within-group values before vs after.

Site of stone (ureteric segment, right/left)
  Upper third 2/43/4
 Middle third4/64/5
 Lower third5/42/7
 Total11/149/16
 Mean (range) age, years35.9 (22–52)41.9 (18–65)
Mean (sd)
Pain score
 Before treatment89.6 (14.8)84.0 (18.0)
 After treatment37.6 (17.8) 22.0 (18.9) *
Heart rate (b.p.m.)
 Before84.8 (10.2)87.6 (11.6)
 After84.0 (7.1)83.6 (8.2)
BP (mmHg)
 Systolic before128.6 (20.6)126.6 (13.7)
 Systolic after123.6 (13.8)120.0 (12.5)
 Diastolic before83.0 (9.1)84.2 (8.6)
 Diastolic after81.0 (8.8)79.2 (9.0)

The mean age of patients, their pain scores, heart rate and systolic and diastolic BP both before and after treatment are compared in Table 1. Patients in group 2 had a significantly lower mean pain score after treatment than had group 1 (P < 0.05). All the other variables were not significantly different (P > 0.05 for each).

The within-group comparison for the variables before and after treatment showed that only the pain score in group 1 was significantly lower after treatment (P < 0.05) ( Table 1). However, in group 2 the pain score was lower and there were slight but statistically significant decreases in heart rate and BP (P < 0.05 for each). None of the patients in group 2 had dizziness, orthostatic hypotension, tachycardia or throbbing headache after using isosorbide dinitrate. There were no adverse reactions after administering tenoxicam in either group.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

To date there have been only two studies of the effects of tenoxicam on renal colic [3,4]. Curry and Kelly [4] reported that tenoxicam was as effective as pethidine in managing acute renal colic, although the onset of action of tenoxicam was slower than that of pethidine. Therefore, they proposed a combination of pethidine and tenoxicam for more severe and persistent pain. In the present study, tenoxicam combined with the transient effect of isosorbide dinitrate was more effective in decreasing the pain score than tenoxicam alone. Isosorbide dinitrate exerts its effects within 2–5 min of sublingual administration and is known to have a plasma half-life of 45–60 min. It is taken up by smooth muscle cells and the nitrate group is cleaved to inorganic nitrite and then to NO. The primary metabolites, isosorbide 2-mononitrate and isosorbide 5-mononitrate, have longer half-lives (2–5 h) and are presumed to be responsible, at least partly, for the therapeutic effect of isosorbide dinitrate [6]. In addition, it has also been shown in in vitro experiments that the NO pathway has a role in ureteric relaxation [7]. Therefore, the effects in the present study might also be a result of this ureteric relaxing effect of isosorbide dinitrate. Another possible mechanism for the decreased pain in patients with renal colic might be the decreased urinary output caused by the reflex sympathetic vasoconstriction of the renal vasculature after administering nitrates, thereby decreasing the intraluminal pressure [8].

To our knowledge, the present study is the first to report a greater effect of tenoxicam in relieving renal colic when used with isosorbide dinitrate; however, the type of interaction between these drugs, whether additive or synergistic, has not been established and needs to be clarified in further studies. In addition, as there was no available knowledge of the clinical effect of isosorbide dinitrate on renal colic, it would have been unethical in the present study to form a group of patients receiving only isosorbide dinitrate. However, after the present pilot study, it would be desirable to carry out another study on more patients, including a third group receiving only isosorbide dinitrate.

There was no significant difference between the present two groups in the haemodynamic variables after treatment, even though there were slight decreases in heart rate and systolic and diastolic BP within group 2. These decreases in BP were within normal limits, and the absence of side-effects such as orthostatic hypotension, tachycardia or headache encourages the use of sublingual isosorbide dinitrate in the immediate management of acute renal colic.

In conclusion, the established effect of tenoxicam in the treatment of severe renal colic could be increased, especially in the emergency setting, with the addition of sublingual isosorbide dinitrate. However, to determine the full effects and interactions of this combination requires a larger study, including a third group of patients receiving only isosorbide dinitrate.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors
  • 1
    Gulmi FA, Felsen D, Vaughan ED. Pathophysiology of urinary tract obstruction. In WalshPC, RetikAB, VaughanED, WeirAJ, eds, Campbell’s Urology, 7th edn. Vol. 1, Chapt. 9. Philadelphia: WB Saunders, 1998: 342 85
  • 2
    Labrecque M, Dostaler LP, Rousselle R, Nguyen T, Poirier S. Efficacy of nonsteroidal anti-inflammatory drugs in the treatment of acute renal colic. Arch Intern Med 1994; 154: 1381 7
  • 3
    Al-waili NSD. Intramuscular tenoxicam to treat acute renal colic. Br J Urol 1996; 77: 15 6
  • 4
    Curry C & Kelly AM. Intravenous tenoxicam for the treatment of renal colic. NZ Med J 1995; 108: 229 30
  • 5
    Katzung BG & Chatterjee K. Vasodilators and the treatment of angina pectoris. In KatzungBG, ed. Basic and Clinical Pharmacology, 7th edn, Chapt 12. Connecticut: Appleton and Lange, 1998: 179 96
  • 6
    Reynolds JEF ed. Martindale: The Extra Pharmacopoeia. 31st edn, London: Pharmaceutical Press, 1996: 893 5
  • 7
    Stief CG, Uckert S, Truss MC, Becker AJ, Machtens S, Jonas U. A possible role for nitric oxide in the regulation of human ureteral smooth muscle tone in vitro. Urol Res 1996; 24: 333 7
  • 8
    Abrams J. Hemodynamic effects of nitroglycerin and long-acting nitrates. Am Heart J 1985; 110 (1 pt 2): 216 24

Authors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. References
  8. Authors

Z. Kekeç, MD, Specialist.

U. Yilmaz, MD, Assistant Professor.

E. Sözüer, MD, Professor.

Editorial comment

These authors report an interesting comparative study investigating the presumed ureteric smooth-muscle relaxant effect of isosorbide dinitrate in patients with acute ureteric colic. The addition of the isosorbide dinitrate significantly lowered pain scores when compared with treatment by prostaglandin inhibitors alone. Somewhat surprisingly, the reduction in pain score seen in both arms of the trial was not accompanied by changes in various cardiovascular variables (Table 1) even though pain scores before treatment were near maximum on a scale defined as ‘the most intractable pain ever felt’. Perhaps some reduction in heart rate after effective treatment might have been expected in group 1.

Isosorbide dinitrate is usually prescribed for angina, having a rapid maximal effect (6–10 min) with a half-life of ≈45 min. Little benefit arising from cardiovascular vasodilatation would be expected after 30 min and it is therefore surprising that the authors chose to measure cardiovascular side-effects (throbbing headache, flushing, orthostatic hypotension) after 30 min, when a more realistic appraisal would have been within 10–15 min of administering the drug.

Generic isosorbide dinitrate is widely available and indicated for the treatment of angina pectoris. Patches (placed distally) are also available to relieve peripheral vascular spasm arising from, e.g. intravenous lines or other apparatus related to venous access. Published evidence for dilatation of human ureteric smooth muscle or trials of the compound in obstructive uropathy are difficult to identify. This compound therefore may be a useful step forward in the management of ureteric colic. However, individual clinicians would have to bear the responsibility for administering the drug, and the recording of cardiovascular side-effects would have to be particularly thorough. It would seem wise at this stage to suggest that the drug is administered under strict protocol control in the context of a clinical trial in patients with acute ureteric colic.

N.J.R. George Senior Lecturer and Consultant Urologist