Int J Clin Exp Med 2017;10(2):3454-3461 www.ijcem.com /ISSN:1940-5901/IJCEM0036943 Original Article Efficacy and safety of combination therapy with drotaverine and ketorolac versus ketorolac monotherapy for acute renal colic: a retrospective study of 322 patients Jie Zhu1*, Yi Cao1*, Meng-Lei Yu1, Cheng Liu3, Wang He3, Bing Zeng4, Jin Li2 Departments of 1Emergency Surgery, 3Urology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou 510120, China; 2Department of Obstetrics and Gynecology, Reproductive Medical Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China; 4Department of Gastrointestinal Surgery, Qingyuan People’s Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Guangdong 511518, China. *Equal contributors and co-first authors. Received July 30, 2016; Accepted December 26, 2016; Epub February 15, 2017; Published February 28, 2017 Abstract: Aim: To investigate the analgesic efficacy and safety of combined therapy using drotaverine and ketorolac vs ketorolac in the treatment of acute renal colic. Methods: This was a retrospective study of a consecutive cohort that included 322 emergency department (ED) patients with a diagnosis of renal colic from our hospital, from June 2014 to September 2015. Pain intensity (PI) was recorded using a visual analog scale (VAS) at different time-points after treatment. The primary outcome was defined as a decrease of 50% or more in the mean PI. The need for rescue analgesics in 120 min and occurrence of adverse effects were considered as secondary outcomes. Results: Of 322 eligible patients, 249 patients were analyzed in this study: 125 patients received ketorolac plus drotaverine and 124 patients received ketorolac only. There were significant differences in PI between the two groups at 30min and 120 min (PI: [OR 1.573, 95% CI: 1.007-3.054, P30 min = 0.047], [OR 2.938, 95% CI: 1.11-7.78, P120 min = 0.03] in multivariable logistic regression) (PI: [OR 1.869, 95% CI: 1.119-3.121, P30 min = 0.017], [OR 2.938, 95% CI: 1.11- 7.78, P120 min = 0.03] in univariable logistic regression). Moreover, significant differences were also found in PI in subgroup analysis of patients with mid and proximal ureteric stones (PI: [OR 3.888, 95% CI: 1.409-10.729, P30 min = 0.009] in multivariable logistic regression) (PI: [OR 3.476, 95% CI: 1.363-8.865, P30 min = 0.009] in univariable logistic regression). Pain relief at 120 min was obtained in 119 patients (95.2%) receiving combined therapy and in 106 patients (85.5%) receiving ketorolac (P = 0.011). Rescue analgesics were required in six patients (4.8%) receiving combined therapy and 18 patients (14.5%) receiving ketorolac (P = 0.009). Adverse events were simi- lar between the two groups: 20 (16%) in the combined group and 16 (13%) in the ketorolac group (P = 0.843). Conclusion: Ketorolac combined with drotaverine is effective in relief of acute renal colic, especially pain due to mid and proximal ureteric lithiasis, but did not decrease PI significantly in renal colic patients with renal and distal ureteral stones. On the other hand, combined therapy with ketorolac and drotaverine was associated with a reduced use of rescue analgesics. Keywords: Analgesia, drotaverine, renal colic, visual analog scale Introduction treatment of acute renal colic involves finding a rapid and effective means of analgesia after Renal colic is an acute syndrome characterized diagnosis [2]. However, the ideal analgesic regi- by severe flank pain arising from obstruction of men for acute renal colic remains controversial the urinary tracts, with a lifetime risk of 12% in ED. The guidelines of the European Associ- in men and 6% in women [1]. The excessive ation of Urology on ureteral calculi suggests pressure stimulates the local release of prosta- the use of nonsteroidal anti-inflammatory drugs glandins, which in turn leads to vasodilatation, (NSAIDs) as a first-line strategy for relieving diuresis, and ureteral spasm. Thus, emergency renal colic, and using opioids as rescue medica- Combination therapy with drotaverine and ketorolac for acute renal colic tion [3]. A large number of studies have recom- used to identify eligible patients. Inclusion cri- mended ketorolac (the first parenteral NSAID teria were: (1) Presenting of acute renal colic available in the United States) as the primary after physician evaluation by auxiliary examina- analgesic for the treatment of renal colic, given tions, such as ultrasonography and non-con- its efficiency in relieving acute pain with fewer trast computed tomography (CT); (2) Visual ana- adverse outcomes and lower costs [1, 4-6]. logue scale (VAS) score ≥ 40 mm. Exclusion criteria: (1) Those who did not undergo ultraso- Regardless of their effective action as analge- nography or CT, or did not reveal a renal or ure- sics for renal colic, a number of adverse events teral stone; (2) Patients who were diagnosed have been associated with NSAIDs, including not only renal but also ureter stones; (3) Pati- nausea, vomiting, rash, dizziness, hypotension, ents who were pregnant or had used any spas- and headache [7]. Failure to relieve pain in molytics or analgesics within the previous 6 h; renal colic, defined as the requirement for (4) Those who had second or third degree atrio- rescue therapy, occurs in 7% to 39% of such ventricular block, malignant disease, renal fail- patients treated with NSAIDs [8]. ure, urogenital anomaly, or hepatic or cardiac insufficiency. To improve the efficiency of NSAIDs as well as to reduce the requirements for rescue analge- Stones in the mid-ureter, but closed to the top, sics, spasmolytics are frequently used for acute were classified into the mid and proximal ureter renal colic by medical practitioners, as they group, and those closer to the bottom were may help to relieve pain by relaxing the smooth included in the distal ureter group. Patients muscle[9]. Drotaverine, a selective phosphodi- who only had renal stones were classified into esterase 4 (PDE IV) inhibitor, has previously the renal group. been shown to be useful in the efficient and Treatments safe treatment of renal colic [10, 11]. Patients who had a clinical diagnosis of sus- The concept of balanced analgesia that has pected acute renal colic after physician evalua- been suggested by earlier studies has proven tion by physical examination were treated with to be the method of choice for achieving suffi- ketorolac plus drotaverine or with ketorolac cient pain reduction by using a combination of only, based on physician decision. In the com- different regimens [12]. In 2006, Safdar et al. bined group, 125 patients received intramus- reported that a combination of morphine and cular ketorolac (60 mg) plus intravenous dro- ketorolac offered pain relief superior to that taverine hydrochloride (80 mg), while in the offered by either drug alone, and was associat- ketorolac group, 124 patients received intra- ed with a decreased requirement for rescue muscular ketorolac (60 mg) only. Rescue thera- analgesics [13]. Regardless of it is an experi- py was defined as the need for morphine if the enced treatment for the co-administration of VAS score at 120 min exceeded 40 mm [14]. drotaverine and ketorolac for pain relief in acute renal colic, there has been no evidence Data collection and endpoints for this combined therapy. Thus, we carried out a retrospective cohort study to investigate Observations and pain scores were recorded whether the addition of drotaverine to ketorolac on a standard datasheet by the treating nurse could improve the efficacy of pain relief in at 0 (baseline), 30, 60 min, and then hourly patients with acute renal colic. until 2 h after commencing treatment. All pati- ents were asked to rate the intensity of their Methods pain on a 0- to 100-mm VAS datasheet, in which 0 indicates “no pain” and 100 indicates Patients and inclusion criteria the “severest imaginable pain”. The primary efficacy endpoint was defined as a relative We conducted a retrospective analysis of 322 decrease of PI between baseline and each adult patients (age: 18-60 years) who reported observation time, calculated as previously de- to the emergency department of Sun Yat-sen scribed [15]: [(PIBaseline-PIx)/PIBaseline)] × Memorial Hospital from June 2014 to Septem- 100%. For example, the mPI 30 min represents ber 2015, with clinical symptoms and signs of the mean reduction in PI across 30 min (VAS at renal colic. Standardized screening tools were baseline-VAS at 30 min). The effectiveness of 3455 Int J Clin Exp Med 2017;10(2):3454-3461 Combination therapy with drotaverine and ketorolac for acute renal colic Statistical analysis Demographic variables, Diag- nostic evaluation, Location of Stone, rescue analgesics and adverse events measured on a categorical scale were sum- marized using quality, frequen- cies and percentages, while continuous variables were su- mmarized in terms of means and standard deviations (SD). Figure 1. Flowchart of patients screened for The comparisons of demogra- the study. phic characteristics between the two cohorts were conduct- ed using two sample t-test or Chi-square test. The compari- sons of History of urinary tra- ct infection, rescue analgesics and adverse events adverse events between study cohorts were performed using Fisher’s exact test. The variation of PI in two cohorts was statistically Table 1. Baseline characteristics of the participants in the study analyzed using the univariable and multivariable and logistic Combined Ketorolac group group P-value regression, adjusted by age, (n = 125) (n = 124) gender, baseline VAS and dur- Age, mean ± SD 39.7 ± 10.2 41.6 ± 9.8 0.1341a ation of pain before visit. Odds ratios (OR) and the correspon- Gender, n (%) 0.475b ding 95% confidence intervals Male 85 (68.0) 79 (63.7) (CI) were reported.