Intramuscular Etofenamate Versus Diclofenac in the Relief of Renal Colic a Randomised, Single-Blind, Comparative Study

Clin Drug Invest 2003; 23 (11): 701-706 ORIGINAL RESEARCH ARTICLE 1173-2563/03/0011-0701/$30.00/0

Intramuscular Etofenamate versus Diclofenac in the Relief of Renal Colic A Randomised, Single-Blind, Comparative Study

Avelino Fraga,1 Martinho de Almeida,2 Vítor Moreira-da-Silva,2 Manuel Sousa- Marques,3 Luís Severo,3 Alberto Matos-Ferreira,4 Luís Campos-Pinheiro,4 Mario´ Reis,5 Ulisses Ribau,5 Pedro Silveira6 and Luís Almeida6

1 Hospital D. Pedro V, Porto, Portugal 2 Hospital Pedro Hispano, Matosinhos, Portugal 3 Hospital do Desterro, Lisbon, Portugal 4 Instituto de Urologia, Lisbon, Portugal 5 Hospital S. Joao,˜ Porto, Portugal 6 R&D Department, Laboratorios Bial, S. Mamede do Coronado, Portugal

Abstract Objective: To compare the efficacy and adverse effects of intramuscular etofenamate and intramuscular diclofenac in the relief of acute renal colic. Patients and methods: A multicentre, randomised, single-blind study was performed in 119 patients admitted to the emergency room for renal colic. Patients were assigned to treatment with either etofenamate 1000mg or diclofenac 75mg, both administered intramuscularly. Pain was self-assessed using a 4-point verbal rating scale (VRS) and a visual analogue scale (VAS) just before drug administration and 30, 60, 120 and 240 min later. Results: The two groups were similar with regard to baseline characteristics. The percentages of patients who reported an improvement in the VRS at 60 min post-administration (primary variable) were 84.5% with etofenamate and 83.3% with diclofenac (p = 0.73). At the other timepoints (30, 120 and 240 min), the proportions of patients improved were, respectively, 69.5%, 82.6% and 79.3% in the etofenamate group, and 75.0%, 81.7% and 80.0% in the diclofenac group. The VAS score showed a statistically significant improvement in both groups, but no differences between groups were found. Analgesic rescue medication was required by 11 (18.6%) patients in the etofenamate group and by 12 (20.0%) patients in the diclofenac group. Mild to moderate adverse events were reported by 3.4% of patients receiving etofenamate and by 5.0% of patients receiving diclofenac. Conclusion: Etofenamate and diclofenac were similarly effective and tolerated in the relief of acute renal colic. 702 Fraga et al.

Renal colic has an annual incidence of approxi- Patients and Methods mately 16 per 10 000 individuals, and a lifetime [1] incidence of 2–5%, and is mainly caused by Study Design and Ethical Approval nephrolithiasis. The passage of stone through the ureter is a common mechanical cause of urinary This was a multicentre, comparative, parallel tract obstruction. When the obstruction is acute, pain group, randomised, single-blind study carried out at emergency care units. The study was conducted is the predominant clinical symptom and is due to according to the principles of the current revision of the distension of the collecting system or renal cap- the Declaration of Helsinki and according to Good sule. The pain begins gradually but increases over Clinical Practice guidelines. An independent Ethics time to become so severe that it is often described as Committee revised and approved the study protocol the worst pain a patient has ever experienced, justi- and the information provided to the patients in each fying the urgent prescription of rapid and effective centre. Written informed consent was obtained for analgesia even before diagnostic confirmation. each patient prior to enrolment in the study. Nonsteroidal anti-inflammatory drugs (NSAIDs) Study Population and Procedures and narcotic analgesics are the most commonly used drugs in the acute relief of renal colic, and both Patients with moderate to severe pain suggestive groups have been shown to be effective in random- of a clinical diagnosis of acute renal colic, who had ised, prospective studies.[2,3] However, narcotics can not taken any analgesic or antispasmodic drugs in cause excessive sedation.[4] The inhibition of cyclo- the previous 2h, were selected. To confirm the diag- oxygenase by NSAIDs decreases prostaglandin pro- nosis of renal colic, patients were observed for spon- duction and, consequently, the smooth muscle ac- taneous voiding of a calculus, and an abdominal x- tivity of the ureteral and renal pelvis, oedema and ray, ultrasonography or urography was performed. Other procedures, such as urinalysis or blood tests, inflammation. The reduction in local oedema and were performed when needed, according to the in- inflammation can have a positive influence in stone vestigator’s judgement. Subjects with pain symp- [5] progression. toms lasting more than 12h, any condition that could Etofenamate is a NSAID of the flufenamic acid constitute a contraindication to NSAIDs, evidence derivative group and possesses strong anti-inflam- of drug addiction, unavailability for completing the matory and analgesic activity. In clinical practice, it pain self-assessment scales, pregnant or lactating is only administered by cutaneous and intramuscular women or women of childbearing potential not us- routes because it has poor oral bioavailability. ing effective contraception were excluded. Eligible patients were randomly assigned to treat- The present study aimed to compare the efficacy ment with a single intramuscular dose of etofena- and adverse effects of intramuscular etofenamate mate (1000mg/2mL, Reumon®1 IM, Laboratorios and diclofenac in the relief of acute renal colic. Bial, S. Mamede do Coronado, Portugal) or diclo- Diclofenac was chosen as the reference product fenac (75mg/3mL, Voltaren® IM, Novartis, Sintra, because its use has been established in the treatment Portugal). A single-blind procedure was followed: of renal colic.[6-8] patients were unaware of which treatment they had

1 The use of tradenames is for product identification purposes only and does not imply endorsement.

Table I. Baseline patient characteristics Etofenamate Diclofenac (n = 59) (n = 60) Sex [n (%)] male 40 (67.8) 36 (60.0) female 19 (32.2) 24 (40.0) Age (y) [mean ± SD (range)] 47.4 ± 17.0 (21–80) 45.0 ± 14.7 (20–73) Height (cm) [mean ± SD (range)] 167.6 ± 8.1 (152–182) 165.3 ± 8.5 (140–180) Weight (kg) [mean ± SD (range)] 75.0 ± 10.8 (55–105) 72.8 ± 11.5 (51–100) VRS pain score [n (%)] severe 37 (62.7) 36 (60.0) moderate 22 (37.3) 24 (40.0) VAS score (mm) [mean ± SD (range)] 80.1 ± 17.7 (30–100) 78.5 ± 16.5 (42–100) VAS = visual analogue scale; VRS = verbal rating scale. been assigned to; blinding of the healthcare person- 60 patients per group will detect differences be- nel was considered to be unfeasible because of the tween treatments, with a level of significance of 5% different characteristics of the two products (vol- and a power of 80%. The secondary efficacy vari- ume, colour and viscosity). ables were the proportion of patients reporting an improvement in the VRS in the 30-, 120- and Pain intensity was self-assessed by the patients 240-min assessments, the evolution of the VAS using a 4-point verbal rating scale (VRS) [0 = ab- score during the study period, and the proportion of sence of pain; 1 = mild pain; 2 = moderate pain; 3 = patients requiring rescue medication. All statistical severe pain] as described elsewhere,[8] and a 100mm tests were two-tailed with a 5% level of significance. visual analogue scale (VAS), in which the left end All patients who were administered medication represented “absence of pain” and the right end were considered for adverse event analysis. The represented the “most painful situation you can ima- statistical package used was Statistica 5.5 (StatSoft, gine”.[9,10] Pain intensity was assessed just before Inc., Tulsa, OK, USA). product administration and 30, 60, 120 and 240 min later. Patients were allowed to receive rescue medication when required, according to the investigator’s judgement. All adverse events spontaneously reported by Etofenamate patients during the study were characterised and Diclofenac 100 recorded. 80

60 Statistical Analysis 40

The primary efficacy parameter defined in the of patients Percentage 0 protocol was the proportion of patients reporting an 30 60 120 240 improvement in the VRS after 60 min. According to Time post-administration (min) Fig. 1. Percentage of patients reporting improvement in the verbal published data and assuming that 85% of diclo- rating scale from baseline after administration of either etofenamate fenac-treated patients will improve, a sample size of or diclofenac in patients with renal colic.

100 Etofenamate Diclofenac respectively. VAS scores remained not significantly 80 different at 120 and 240 min. 60 Analgesic rescue medication was required by 11 40 (18.6%) patients in the etofenamate group and by 12

VAS score (mm) VAS 20 (20.0%) patients in the diclofenac group (figure 3).

0 The decision to administer rescue medication was 03060 120 240 based on the investigator’s judgement, taking into Time post-administration (min) account the severity of pain. Drugs and doses used Fig. 2. Evolution of the visual analogue scale (VAS) score following administration of either etofenamate or diclofenac in patients with were decided according to the centre protocols for renal colic. treatment of acute renal colic in clinical routine. Pethidine (n = 13), with or without metoclopramide, Results was the most used rescue analgesic, followed by tramadol (n = 5), with or without metoclopramide. Paracetamol (n = 2) and other NSAIDs, and Efficacy dipyrone or thiocolchicoside were also used. One patient in the etofenamate group who had reported A total of 119 patients were enrolled in the study significant improvement at the 30-min evaluation and were randomly assigned to treatment with either unexpectedly left the emergency care unit before the etofenamate (n = 59) or diclofenac (n = 60). Groups 60-min evaluation. were similar with regard to baseline characteristics (table I). Most of the patients were diagnosed by means of abdominal x-ray (82.4%) and/or ultra- Tolerability sonography (69%). Fourteen (11.8%) patients spontaneously voided a calculus and four (3.4%) were In the etofenamate group, a total of two adverse submitted to urography. events (somnolence and pain at the injection site) No significant difference was found between the were reported by two (3.4%) patients. In the diclo- treatments with regard to the primary efficacy para- fenac group, three (5.0%) patients reported a total of meter: at 60 min, the VRS showed that 84.5% of five adverse events (upper abdominal pain [n = 2], patients treated with etofenamate and 83.3% treated nausea, vomiting and somnolence). All adverse with diclofenac had improved (figure 1) [p = 0.73; χ2 test]. At the other timepoints (30, 120 and 240 Etofenamate 25 Diclofenac min), the proportions of patients improved were, respectively, 69.5%, 82.6% and 79.3% in the 20 etofenamate group and 75.0%, 81.7% and 80.0% in 15 the diclofenac group (figure 1). 10 The VAS score showed a statistically significant improvement in both groups (figure 2). At 30 and 60 5 Percentage of patients Percentage min, the average VAS scores were, respectively, 0 40.7 ± 27.8 and 33.2 ± 25.3 (95% CI 33.6–47.8; 30 60 120 240 26.7–39.7; not significant) and 23.1 ± 26.5 and 18.3 Time post-administration (mins) ± Fig. 3. Cumulative percentage of patients requiring analgesic res- 24.9 (95% CI 16.1–30.1; 11.7–24.9; not signif- cue medication following administration of either etofenamate or icant) in the etofenamate and diclofenac groups, diclofenac in patients with renal colic.

events were mild to moderate in intensity and no guaranteed because the active moiety is rapidly withdrawal due to adverse events was reported. cleared. In contrast, plasma concentrations of etofenamate, an oily solution, increase less rapidly, Discussion reaching a plateau 2h post-administration. Relative- ly high plasma levels persist for up to 10h, probably The efficacy of intramuscular etofenamate in because of a ‘depot-like’ phenomenon resulting several painful conditions has been confirmed in a from the oily nature of the solution.[19] Theoretical- number of controlled studies, including those com- ly, this profile would allow a more prolonged action paring intramuscular indomethacin in the treatment when compared with diclofenac. [11] of postoperative pain and swelling, and those Both etofenamate and diclofenac markedly im- comparing intramuscular diclofenac in the treatment proved pain in all efficacy variables. Pain relief [12] of fresh blunt injuries and the acute lumbar syn- obtained with diclofenac in this study was consistent [13] drome. To date, only one exploratory open-label with that reported in the literature.[7,8,20] No statisti- study with etofenamate in renal colic has been re- cally significant differences were found between the [14] ported. Our study aimed to obtain additional evi- groups in any of the efficacy variables. dence about the potential usefulness of etofenamate Diclofenac and etofenamate were well tolerated; in this indication, comparing it with a standard only a few mild to moderate side effects were report- NSAID. In spite of some concerns about the use of ed, consistent with the known adverse event profile intramuscular diclofenac, such as delay in renal of the drugs. transit time[15] or exacerbation of pain as a result of the injection,[16] it was chosen as the comparator Conclusion because it is widely used and is considered a treatment of choice in acute renal colic by some investi- In conclusion, the results of this single-blind, gators.[6,17] randomised, controlled study confirm previous pre- A single-blind design was used because the dis- liminary evidence that intramuscular etofenamate is tinct product visual characteristics (volume, colour a useful option in the treatment of patients with and viscosity) made blinding of the healthcare per- acute renal colic. sonnel unfeasible. A double-blind design would Acknowledgements have been preferable, but was not possible to imple- ment because of logistic constraints. However, the This study was supported by a grant from Bial – Portela & efficacy variables of this study were dependent on Cª, SA, Portugal. self-assessment scales (VRS and VAS) and, there- fore, the chance of bias was minimised. These scales References 1. Holdgate A, Hardcastle J. Renal colic: a diagnostic and thera- have been frequently used in similar studies and are peutic review. Emerg Med 1999; 11: 9-16 generally considered to be reliable tools in the as- 2. Cordell WH, Larson TA, Lingeman JE, et al. Indomethacin sessment of subjective symptoms such as pain.[10] suppositories versus intravenously titrated morphine for the treatment of ureteral colic. Ann Emerg Med 1994; 23: 262-9 After intramuscular injection of diclofenac, an 3. Uden P, Rentzhog L, Berger T. A comparative study on the aqueous solution, maximum plasma concentrations analgesic effects of indomethacin and hydromorphinechloride- atropine in acute, ureteral-stone pain. Acta Chir Scand 1983; occur at 20–30 min post-administration and decline 149: 497-9 rapidly, with an elimination half-life of 1.15h.[18] 4. Gulmi FA, Felsen D, Vaughan ED. Pathophysiology of urinary tract obstruction. In: Walsh PC, Retik AB, Vaughan ED, et al., This pharmacokinetic profile is consistent with a editors. Campbell’s urology. 7th ed. Vol. 1. Philadelphia (PA): rapid onset of action, but no sustained effects are WB Saunders, 1998: 342-85

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