Endourological Modalities and Pharmacological Treatment of Ureteral Stones

Burden of Ureter Stone Disease: An Overview

Ureter stone disease or ureterolithiasis is one of the most common conditions seen in the emergency department. The prevalence, incidence and distribution of this stone disease vary across geographies, but both developed and developing nations appear to share the disease burden of this urological construct that has been estimated to have a lifetime prevalence of about 10% to 15%.¹Kennish SJ, Wah TM, Irving HC. Unenhanced CT for the evaluation of acute ureteric colic: the essential pictorial guide. Postgrad Med J. 2010 Jul;86(1017):428-36.   ²Heidenreich A, Desgrandschamps F, Terrier F. Modern approach of diagnosis and management of acute flank pain: review of all imaging modalities. Eur Urol. 2002;41(4):351-62.   ³Otal P, Irsutti M, Chabbert V, Murat C, Ducassé JL, Rousseau H, Joffre F. Radiologic study of renal colic. J Radiol. 2001;82(1):27-33.   ⁴Smith RC, Levine J, Dalrymple NC, Barish M, Rosenfield AT. Acute flank pain: a modern approach to diagnosis and management. Semin Ultrasound CT MR. 1999;20(2):108-35.   ⁵Tchey DU, Ha YS, Kim WT, Yun SJ, Lee SC, Kim WJ. Expectant Management of Ureter Stones: Outcome and Clinical Factors of Spontaneous Passage in a Single Institution’s Experience. Korean J Urol. 2011; 52(12): 847-851.   ⁶Trinchieri A. Epidemiology of urolithiasis: an update. Clinical cases in mineral and bone metabolism 2008;5(2):101-106.   This high prevalence, coupled with the recurrent and unpredictable nature of stone disease, and its predominance in working age adults, contributes to the substantial impact on the individual, healthcare systems, and the society.⁷Morgan MSC, Pearle MS. Medical management of renal stones. BMJ 2016;352:i52.   Especially, it is observed that countries in the Afro-Asian stone belt (stretching from Egypt and Sudan, through the Middle East, India, Pakistan, Burma, Thailand, Indonesia and the Philippines), which fall within the tropical and subtropical regions, and generally have high population density, have high incidence of stone disease.⁸Rizvi SAH, Naqvi SAA, Hussain Z, Hashmi A, Hussain M, Zafar MN, Mehdi H, Khalid R. The management of stone disease. BJU International 2002;89(Suppl s1):62-68.   As such, the burden of ureterolithiasis would indeed be higher in this region that includes significant part of the Indian subcontinent.

Usually, acute flank pain or severe renal colic is the most characteristic clinical feature in patients with ureter stone disease, which occurs due to sudden obstruction of the ureter by the stone. In such events, imaging – often used in context of clinical features – usually helps in clinical decision making, and the majority of cases of acute ureteric colic can be correctly classified in emergency by clinical characteristics of acute onset, flank pain, hematuria, and positive radiograph of the kidney, ureter, and bladder (KUB).⁹Elton TJ, Roth CS, Berquist TH, Silverstein MD. A clinical prediction rule for the diagnosis of ureteral calculi in emergency departments. J Gen Intern Med. 1993;8(2):57-62.   ¹⁰Wang CC, Liao CH, Kuo HC. Clinical guidelines for male lower urinary tract symptoms associated with non-neurogenic overactive bladder. Urological Science 2015;26(1):7-16.   Nevertheless, while an expectant approach is generally the preferred initial strategy, more than one-third of patients with ureter stone disease have difficulty passing their stone, and frequently require an intervention for definite outcomes.

Impact of Ureter Stone Disease on Quality of Life

Ureteral stone disease is associated with severe physical and psychological effects that lead to clinically significant impairment in quality-of-life of the affected individuals, and may limit their vocational responsibilities.¹¹Rabah DM, Alomar M, Binsaleh S, Arafa MA. Health related quality of life in ureteral stone patients: post-ureterolithiasis. Urol Res. 2011;39(5):385-8.   ¹²Nuss GR, Rackley JD, Assimos DG. Adjunctive Therapy to Promote Stone Passage. Rev Urol. 2005 Spring; 7(2): 67-74.   Not only it causes significant pain and suffering, but the impact can be perceived in several other ways, for instance through variables such as surgical complications, time from last stone episode, number of emergency room visits, and number of surgeries. In fact, this overall impact seems to validate the hypothesis that patients with multiple recurrent episodes of urolithiasis have worse health related quality of life, which per se is a promising end point in the management of urolithiasis.¹¹Rabah DM, Alomar M, Binsaleh S, Arafa MA. Health related quality of life in ureteral stone patients: post-ureterolithiasis. Urol Res. 2011;39(5):385-8.   ¹³Bryant M, Angell J, Tu H, Goodman M, Pattaras J, Ogan K. Health related quality of life for stone formers. J Urol. 2012;188(2):436-40.  

Management of Ureteral Stones with Minimally Invasive Endourological Procedures

The modern management of urolithiasis requires a multi-disciplinary approach, with imaging playing a central role in both diagnosis and planning of the therapy.¹⁴Sandhu C, Anson KM, Patel U. Urinary tract stones–Part I: role of radiological imaging in diagnosis and treatment planning. Clin Radiol. 2003;58(6):415-21.   The next step in the work-up is the treatment decision that is mainly based on stone size and position, and influenced by expectations of the patient and experience of the surgeon.¹Kennish SJ, Wah TM, Irving HC. Unenhanced CT for the evaluation of acute ureteric colic: the essential pictorial guide. Postgrad Med J. 2010 Jul;86(1017):428-36.  ¹⁵Morse RM, Resnick MI. Ureteral calculi: natural history and treatment in an era of advanced technology. J Urol. 1991;145(2):263-5.   Both medical and surgical methods have evolved for this clinical need, and now a variety of expectant, non-invasive and invasive approaches, such as medical expulsive therapy, ureteroscopy, shock wave lithotripsy, and laparoscopic ureterolithotomy, are available, which may be selected for best outcomes in individual patients.¹⁶Wolf JS Jr. Treatment selection and outcomes: ureteral calculi. Urol Clin North Am. 2007;34(3):421-30.  

Generally, watchful waiting and conservative methods are initial steps in many cases, and are often preferred by patients. However, the strategy might not suit the clinical requirement in individual cases, seeing that almost 40% of patients with ureter stone disease have difficulty passing their stone; the more proximal the location and the larger the stone, the less are the chances of spontaneous passage.¹Kennish SJ, Wah TM, Irving HC. Unenhanced CT for the evaluation of acute ureteric colic: the essential pictorial guide. Postgrad Med J. 2010 Jul;86(1017):428-36.   As a general rule, most stones ≤4 mm in diameter pass spontaneously, while stone diameter ≥5 mm is associated with a progressive decrease in the spontaneous passage rate; spontaneous passage of stone is unlikely with stones ≥10 mm in diameter.¹⁷Preminger GM, Goldfarb S, O’Leary MO, Forman JP. Management of ureteral calculi. Available at: http://www. uptodate.com/contents/management-of-ureteral-calculi [Accessed on 2/5/2016].   Likewise, proximal ureteral stones are also less likely to pass spontaneously. These patients often require an intervention, and may benefit from variety of surgical methods to be selected primarily based on the stone size and location.¹Kennish SJ, Wah TM, Irving HC. Unenhanced CT for the evaluation of acute ureteric colic: the essential pictorial guide. Postgrad Med J. 2010 Jul;86(1017):428-36.   A particular point of interest in this therapeutic arm has evolved in form of real-time visualization of the urological tract to facilitate removal of the stones. In fact, it is seen that the endoscopically based techniques have virtually revolutionized this specialty over the past few decades with development of endourological equipment and improving skills with these modalities. As follows, minimal access or minimally invasive endoscopic surgery is now a commonplace for considerable segments of surgical procedures across the specialty lines, and this has greatly diminished the role of open surgery in managing ureteric calculi.¹⁸Fuchs GJ. Milestones in endoscope design for minimally invasive urologic surgery: the sentinel role of a pioneer. Surg Endosc. 2006 Apr;20 Suppl 2:S493-9.   Trends over more than 10 years in managing ureteric calculi also show a considerable decline in indications for open surgery, citing recent advances in endourology as a major factor for this transition. Table 1 depicts certain inherent advantages of minimally invasive surgery.¹⁹Ather MH, Paryani J, Memon A, Sulaiman MN. A 10-year experience of managing ureteric calculi: changing trends towards endourological intervention is there a role for open surgery? BJU International 2001;88:173-177.  

Ureteroscopy

During the past three decades, ureterorenoscopy has dramatically changed the management of ureteral calculi and is now extensively used in many urological centres all over the world. The method has evolved into a safer and more efficacious modality for treatment of stones in all locations in ureter, with increasing experience world-wide. This has perhaps become possible because of development of smaller caliber semi-rigid and flexible ureteroscopes and introduction of improved stone retrieval instrumentation. Although, the method is invasive in nature, in the hands of an experienced urologist it proves to be a highly effective procedure, with success rates approaching 100% in the distal ureter and negligible retreatment rates, and widespread availability.²⁰Etafy M, Morsi GAM, Beshir MSM, Soliman SS, Galal HA, Ortiz-Vanderdys C. Management of lower ureteric stones: a prospective study. Cent European J Urol. 2013; 66(4): 456-462.  

Especially, ureteroscopy has constituted the favoured approach for surgical treatment of distal and mid ureteral stones, but with improved efficacy and reduced morbidity associated with ureteroscopic management of proximal ureteral stones, this modality may now be deemed appropriate for stones of any size at any site in the ureter. The overall stone-free rates are remarkably high at 81% to 94% depending on stone location, and vast majority of patients are rendered stone free in a single procedure.²¹Preminger GM, Tiselius HG, Assimos DG, Alken P, Buck C, Gallucci M, Knoll T, Lingeman JE, Nakada SY, Pearle MS, Sarica K, Turk C, Stuart Wolf J Jr. Management of ureteral calculi: EAU/AUA nephrolithiasis panel (2007). Available at: https://www.auanet.org/education/guidelines/ureteralcalculi.cfm#89 [Accessed on 2/5/2016].   In addition, the complication rates, most notably ureteral perforation rates, have been reduced to < 5%, while long-term complications, such as stricture formation, occur with an incidence of ≤ 2%. Mainly the flexible ureteroscope is responsible for improved access to the ureter and high stone-free success rates, and might be particularly effective for treatment of proximal ureteral calculi. Though a rigid or semirigid ureteroscope might be more successful for large distal ureteral stones, particularly those >10 mm.21 Furthermore, ureteroscopy can also be applied when shock-wave lithotripsy might be contraindicated or ill- advised. In emergency as well, ureteroscopy in cases of obstructive ureteral stones has proved to be safe and effective, with main advantage of offering both immediate relief from pain and stone fragmentation.²²Osorio L, Lima E, Soares J, Autorino R, Versos R, Lhamas A, Marcelo F. Emergency ureteroscopic management of ureteral stones: why not? Urology. 2007;69(1):27-31;discussion 31-3.   Particularly, a greater stone-free rate was obtained in those with stones < 10 mm, and in those with stones located in the distal ureter. Overall, the new generation of smaller-calibre ureteroscopes can be used by experienced hands for treatment of proximal as well as distal ureteric stones.²³Bartoletti R, Cai T. Surgical approach to urolithiasis: the state of art. Clin Cases Miner Bone Metab. 2008; 5(2): 142-144.   ²⁴Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wp-content/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].  

Role of Tamsulosin as a Medical Expelling Agent in Success of Endourological Procedure

In emergency situations, urgent decompression of collecting system, together with appropriate antimicrobial therapy, is indicated in septic patients with obstructing stones, while definitive treatment is delayed until sepsis is resolved.¹⁷Preminger GM, Goldfarb S, O’Leary MO, Forman JP. Management of ureteral calculi. Available at: http://www. uptodate.com/contents/management-of-ureteral-calculi [Accessed on 2/5/2016].   Few other indications for urgent decompression include bilateral obstruction with acute kidney injury (AKI), and unilateral obstruction with AKI in a solitary kidney. Nevertheless, in most other instances, the clinical picture involves patients with a newly diagnosed ureteral stone ¹⁷Preminger GM, Goldfarb S, O’Leary MO, Forman JP. Management of ureteral calculi. Available at: http://www. uptodate.com/contents/management-of-ureteral-calculi [Accessed on 2/5/2016].  

With ureteroscopy, improving the stone-free rates can further decrease the need for ancillary procedures and improve patient outcomes and satisfaction. In practice, this may be facilitated by use of medical expulsive therapy after ureteroscopy, which not only increases stone free rates, but reduces colic episodes as well. Especially, medical expulsive therapy can be used to improve stone-free results with ureteroscopy if active fragment removal is not undertaken.²⁵Reddy TG, Assimos DG. Optimizing Stone-free Rates With Ureteroscopy. Rev Urol. 2015;17(3):160-164.   In a prospective randomized controlled clinical trial, Ketabchi and Mehrabi²⁶Ketabchi AA, Mehrabi S. The effect of Tamsulosin, an alpha-1 receptor antagonist as a medical expelling agent in success rate of ureteroscopic lithotripsy. Nephrourol Mon. 2013;6(1):e12836.   assessed the efficacy of Tamsulosin for improving the success rate of ureteroscopic lithotripsy for lower ureteral stones, and observed that Tamsulosin treatment group had higher stone-free rate (93.3% vs. 70%; Figure 1), low expulsion time, low urinary tract symptoms (13.46% vs. 44%), low analgesic needs (7.69% vs. 24%), less colic episodes (mean ± SD, 1 ± 0.7 vs. 6 ± 3.5) and low adverse effects, all with statistically significant differences comparable with the control group (placebo). The study enrolled 142 subjects with lower ureter stone 5-10 mm diameter, out of which 102 patients completed the clinical trial, and underwent ureteroscopic lithotripsy with the pneumatic wolf lithotripsy. The patients were randomly divided into two groups: the study group included 52 patients who received Tamsulosin with traditional treatment (hydration and analgesic when required), and the control group included 50 patients who received placebo with traditional treatment.

In another prospective study, John and Razdan²⁷John TT, Razdan S. Adjunctive Tamsulosin improves stone free rate after ureteroscopic lithotripsy of large renal and ureteric calculi: a prospective randomized study. Urology. 2010;75(5):1040-2.   evaluated the role of Tamsulosin on the stone free rate and the rate of colic episodes after ureteroscopic laser lithotripsy in patients harbouring 10 to 20 mm renal or ureteral stones. The results showed that of the 73 patients available for follow up, the stone free rate was 86.5% in the study group [Tamsulosin (0.4 mg) and standard analgesia (Tylenol with Codeine)], compared with 69.4% in the control group (standard analgesia only). In addition, only 5.4% of the study (Tamsulosin) group had colic episodes, in comparison to 22.2% of the control group. These differences were statistically significant. Thus, it showed that treatment with Tamsulosin improved the stone free rate and reduced the occurrence of colic episodes, after ureteroscopic laser lithotripsy of large renal and ureteric calculi.

Tamsulosin: The Preferred Alpha-Blocker

Alpha-blockade is the main mode of medical expulsive therapy use to accelerate the process of spontaneous passage of stones. The rationale is based on capability of alpha-antagonists in decreasing the force of ureteral contraction, decreasing the frequency of peristaltic contractions, and increasing the fluid bolus volume transported down the ureter.²⁸Lipkin M, Shah O. The Use of Alpha-Blockers for the Treatment of Nephrolithiasis. Rev Urol. 2006;8(Suppl 4):S35-S42.   Meta-analyses have shown that patients with ureteral stones treated with α-blockers or Nifedipine are more likely to pass stones with fewer colic episodes than those not receiving such therapy. However, the recent guidelines from European Association of Urology (EAU) show Tamsulosin – one of the most commonly used alphablockers – to be significantly better than Nifedipine in relieving renal colic and facilitating and accelerating ureteral stone expulsion.²⁴Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wp-content/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].  

Especially, the EAU guidelines depict that a combination of alkalinization use together with Tamsulosin may help to achieve considerably high stone free rates for distal ureteral stones.²⁴Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wp-content/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].   The evidence is based on a prospective, double blind randomized controlled trial that showed that the use of urinary alkalization (Potassium Citrate, which also helps in reducing stone recurrence rates in calcium stone formers)⁷Morgan MSC, Pearle MS. Medical management of renal stones. BMJ 2016;352:i52.   with Tamsulosin could increase the frequency of spontaneous passage of distal ureteral uric acid stones especially those of large size (8-11 mm) (Figure 2).²⁹El-Gamal O, El-Bendary M, Ragab M, Rasheed M. Role of combined use of Potassium Citrate and Tamsulosin in the management of uric acid distal ureteral calculi. Urol Res. 2012;40(3):219-24.   Though Tamsulosin can also facilitate the spontaneous passage of stones ³⁰Yencilek F, Erturhan S, Canguven O, Koyuncu H, Erol B, Sarica K. Does Tamsulosin change the management of proximally located ureteral stones?? Urol Res. 2010 Jun;38(3):195-9.   The drug in fact seems to support the ureteric stone passage in both adults and children in an effective and welltolerated manner.²⁴Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wp-content/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].   ³¹Tasian GE, Cost NG, Granberg CF, Pulido JE, Rivera M, Schwen Z, Schulte M, Fox JA. Tamsulosin and the spontaneous passage of ureteral stones in children: A multi-institutional cohort study. J Urol. 2014; 192(2): 506-511.   ³²Aldaqadossi HA, Shaker H, Saifelnasr M, Gaber M. Efficacy and safety of Tamsulosin as a medical expulsive therapy for stones in children. Arab J Urol. 2015; 13(2): 107-111.   A recent meta-analysis of 12 randomized controlled trials consisting of 4,961 patients concludes that Tamsulosin should be the first drug to be recommended to patients willing to receive medical expulsive therapy. Tamsulosin showed an overall superiority to Nifedipine for distal ureteral calculi ³³Wang H, Man LB, Huang GL, Li GZ, Wang JW. Comparative efficacy of Tamsulosin versus Nifedipine for distal ureteral calculi: a meta-analysis. Drug Design, Development and Therapy 2015 ;10:1257-1265.   Furthermore, alpha-blockers also reduce the morbidity of ureteral stents, with evidence showing improvement of ureteral stent tolerability with Tamsulosin.²⁴Turk C, Knoll T, Petrik A, Sarica K, Skolarikos A, Straub M, Seitz C. Guidelines on Urolithiasis. European Association of Urology 2015. Available at: http://uroweb.org/wp-content/ uploads/22-Urolithiasis_LR_full.pdf [Accessed on 2/5/2016].  

Pain Alleviation: An Important Variable Impacting Overall Quality-of-Life

Pain is an important variable that may impact the choice of therapy in patients with colic episodes. In general, while conservative approach is the initial choice, patients who go for an attempt at medical expulsive therapy are required to have well-controlled pain besides adequate renal functional reserve and no clinical evidence of sepsis. Especially, in cases of urinary stasis cased by stones inhibiting the urine flow, which is accompanied by intense pain, the first step is to relieve pain and spasm, or at least reduce the intensity. In such situations, parasympathetic symptoms accompanying spasm, such as nausea, vomiting, feeling of collapse, impulse to urinate and defecate, debilitate the patient.³⁴Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of Drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6.   However, it is important that patients be examined in a state free of spasm, and it is only thereafter that the mode of definite treating the stone can be selected, i.e. whether to wait for spontaneous passage or to remove it by endoscopy or shock wave lithotripsy. Usually, endoscopic removal is justified in cases of cumulative spasm, even if the stone otherwise would be suitable for spontaneous evacuation. Herein, extracorporeal shock wave lithotripsy (ESWL) has a disadvantage that after the procedure, passage of the stone fragments may be accompanied by spasms. Overall, spasmolysis is therefore required in all cases of ureteric colic.³⁴Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of Drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6.  

Evidence in above section clearly shows that Tamsulosin used for medical expulsion therapy not only helps to enhance the spontaneous passage of stones, but provides considerable decrease in colic episodes as well. In one such study, Dellabella³⁵Dellabella M, Milanese G, Muzzonigro G. Efficacy of Tamsulosin in the medical management of juxtavesical ureteral stones. J Urol. 2003;170: 2202-5.   and colleagues evaluated the efficacy of Tamsulosin for medical expulsive therapy in patients with ureteral colic due to juxtavesical stones in 60 consecutive symptomatic patients with stones located in the juxtavesical tract of the ureter. The findings revealed that Tamsulosin used as a spasmolytic drug during renal colic due to juxtavesical calculi could increased the stone expulsion rate up to 100%. In addition, it decreased the expulsion time, the need for hospitalization and endoscopic procedures. Particularly, Tamsulosin provided good control of the colic pain, and the mean number of analgesic injections was also less for the Tamsulosin group. This pain-alleviating effect of Tamsulosin is significant, though it may be enhanced further with use of other potent analgesics, including non-steroidal anti-inflammatory drugs (NSAIDs) and spasmolytic drugs, such as Drotaverine. In all, the intent is to target the muscle spasm, which is a common cause of pain in the postoperative period.

In this event, Drotaverine has emerged as a well established directly acting, smooth muscle antispasmodic agent that brings about quick and effective pain relief by inhibiting the enzyme phosphodiesterase IV and calmodulin.³⁶Vinod KM, Ashish D. Oral Drotaverine and Aceclofenac Combination versus Aceclofenac alone for Postoperative Pain Relief: A Prospective Randomized Clinical Trial. Indian Journal of Pharmacy Practice 2013 ;6(4):18-21.   In fact, its effects have been confirmed for over 35 years by clinical studies on more than 10 000 patients.³⁴Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of Drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU Int. 2003 Jul;92(1):92-6.   Per se, the isoenzyme phosphodiesterase IV has shown dominance over other phosphodiesterases in regulation of ureteral smooth muscle, and is hence a major target for alleviation of ureteral smooth muscle spasm and pain.³⁷Dash A, Maiti R, Akantappa Bandakkanavar TK, Arora P. Intramuscular Drotaverine and Diclofenac in acute renal colic: a comparative study of analgesic efficacy and safety. Pain Med. 2012;13(3):466-71.  

In clinical practice, a significant advantage of Drotaverine is that it is devoid of any anticholinergic side effects, unlike other available spasmolytics like Dicyclomine.³⁶Vinod KM, Ashish D. Oral Drotaverine and Aceclofenac Combination versus Aceclofenac alone for Postoperative Pain Relief: A Prospective Randomized Clinical Trial. Indian Journal of Pharmacy Practice 2013 ;6(4):18-21.   As well, the efficacy and safety of Drotaverine as analgesic in colic episodes is noninferior to Diclofenac. In a randomized, single-blind study, wherein patients presenting to the emergency department with a colic episode received Drotaverine (80 mg IM) or Diclofenac (75 mg IM), after 30 minutes of drug administration, the visual analog scale (VAS) decreased significantly in both the groups. Furthermore, 90% patients in the Drotaverine group and 88% in the Diclofenac group found the therapy effective (Figure 3).³⁷Dash A, Maiti R, Akantappa Bandakkanavar TK, Arora P. Intramuscular Drotaverine and Diclofenac in acute renal colic: a comparative study of analgesic efficacy and safety. Pain Med. 2012;13(3):466-71.   Therefore, Drotaverine may be used as an effective alternative or add-on therapy in such instances to provide an augmented effect.

Not only in emergency situations, but Drotaverine provides effective pain-control in post operative situations as well. Herein, the drug may be combined with a NSAID, such as Aceclofenac, to provide comprehensive coverage of pain related or unrelated to secondary spasm where several inflammatory mediators are involved. Aceclofenac is a long acting, well tolerated NSAID with lower incidence of side effects and established safety profile, which provides sustained pain relief by preferentially blocking Cyclooxygenase (COX) II enzyme. This profile in fact makes Aceclofenac an ideal NSAID for combining with the fast acting Drotaverine, for effective pain relief from postoperative procedures; the two drugs are complimentary for effective pain relief. A prospective randomized clinical trial from Delhi (India) also documented this efficacy of combination of Drotaverine with Aceclofenac combination in treatment of postoperative pain. Patients receiving Drotaverine (80 mg) and Aceclofenac (100 mg) combination showed statistically significant reduction in pain scores at day 1, 3 and 5, postoperatively.³⁶Vinod KM, Ashish D. Oral Drotaverine and Aceclofenac Combination versus Aceclofenac alone for Postoperative Pain Relief: A Prospective Randomized Clinical Trial. Indian Journal of Pharmacy Practice 2013 ;6(4):18-21.   The combination of Drotaverine and Aceclofenac thus helps to break the vicious circle of pain, spasm and inflammation, leading to better efficacy. Drotaverine and Aceclofenac can be given in cases of renal colic, ureteric colic, post-lithotripsy and in cases of post surgical spasm. This is to ensure fast onset of pain relief in pain due to renal and ureteric stones.

Drotaverine Plus Mefenamic Acid

Similar to the fixed dose combination (FDC) of Drotaverine and Aceclofenac, FDC of Drotaverine and Mefenamic Acid is also highly effective in relief of acute spasmodic pain.³⁸Porwal A, Mahajan AD, Oswal DS, et al. Efficacy and tolerability of fixed-dose combination of dexketoprofen and Dicyclomine injection in acute renal colic. Pain Research and Treatment 2012 (2012);Article ID 295926:5 pages.   A double blinded placebo controlled randomized trial evaluated the effect of premedication with oral Drotaverine-Mefenamic Acid on pain perception during uro-gynecological procedure in 56 women in an outpatient setting.³⁹Sharma JB, Agarwal M, Karmakar D, et al. Evaluation of an effective and cheap analgesic protocol prior to intrauterine device insertion in a developing country. Int J Reprod Contracept Obstet Gynecol . 2015; 4(4):1061-1065.   The findings revealed a significant difference in pain scores among the two groups during the procedure, 15 minutes later and 30 minutes later. No significant adverse effects were observed. A post hoc analysis revealed adequate power, suggesting oral DrotaverineMefenamic Acid an effective option for analgesia during outpatient uro-gynecological procedure that causes spasmodic pain. Alike evidence on efficacy of oral Drotaverine with Mefenamic Acid was shown in another open randomized trial that evaluated effect of the combination on pain perception during another office based uro-gynecological procedure, and compared it with that of paracervical block using 1% Lignocaine and with that of intravenous sedation using Diazepam with Pentazocine in 120 women randomized into three groups.⁴⁰Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S. Comparison of efficacy of oral Drotaverine plus Mefenamic Acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009;63(6):244-52.   The results showed a statistically significant difference in pain scores among the three groups during the procedure, at 30 minutes and at 60 minutes. Oral Drotaverine with Mefenamic Acid was effective in women undergoing office based uro-gynecological procedure associated with pain and spasm.

References

1. Kennish SJ, Wah TM, Irving HC. Unenhanced CT for the evaluation of acute ureteric colic: the essential pictorial guide. Postgrad Med J. 2010 Jul;86(1017):428-36.
2. Heidenreich A, Desgrandschamps F, Terrier F. Modern approach of diagnosis and management of acute flank pain: review of all imaging modalities. Eur Urol. 2002;41(4):351-62.
3. Otal P, Irsutti M, Chabbert V, Murat C, Ducassé JL, Rousseau H, Joffre F. Radiologic study of renal colic. J Radiol. 2001;82(1):27-33.
4. Smith RC, Levine J, Dalrymple NC, Barish M, Rosenfield AT. Acute flank pain: a modern approach to diagnosis and management. Semin Ultrasound CT MR. 1999;20(2):108-35.
5. Tchey DU, Ha YS, Kim WT, Yun SJ, Lee SC, Kim WJ. Expectant Management of Ureter Stones: Outcome and Clinical Factors of Spontaneous Passage in a Single Institution’s Experience. Korean J Urol. 2011; 52(12): 847-851.
6. Trinchieri A. Epidemiology of urolithiasis: an update. Clinical cases in mineral and bone metabolism 2008;5(2):101-106.
7. Morgan MSC, Pearle MS. Medical management of renal stones. BMJ 2016;352:i52.
8. Rizvi SAH, Naqvi SAA, Hussain Z, Hashmi A, Hussain M, Zafar MN, Mehdi H, Khalid R. The management of stone disease. BJU International 2002;89(Suppl s1):62-68.
9. Elton TJ, Roth CS, Berquist TH, Silverstein MD. A clinical prediction rule for the diagnosis of ureteral calculi in emergency departments. J Gen Intern Med. 1993;8(2):57-62.
10. Wang CC, Liao CH, Kuo HC. Clinical guidelines for male lower urinary tract symptoms associated with non-neurogenic overactive bladder. Urological Science 2015;26(1):7-16.
11. Rabah DM, Alomar M, Binsaleh S, Arafa MA. Health related quality of life in ureteral stone patients: post-ureterolithiasis. Urol Res. 2011;39(5):385-8.
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