Special Issue "Non-Steroidal Anti-Inflammatory Drugs"

Guest Editor
Prof. Dr. Jane McHowat
Department of Pathology, Saint Louis University School of Medicine, Doisy Research Building, 1100 S Grand Blvd, St. Louis, MO 63104, USA
E-Mail:
Interests: The role of the endothelium in platelet-activating factor production and transendothelial cell migration of inflammatory cells.

Dear Colleagues,

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs worldwide and are an important class of drugs used to treat inflammatory conditions. NSAIDs are used to treat pain and inflammation in a variety of conditions and produce their effect by inhibition of cyclooxygenase (COX). A major drawback of NSAID use is the high incidence of gastrointestinal side effects, which lead to the development of the selective COX-2 inhibitors in the 1990s. In spite of the advances in NSAID development over the past few years, the availability of a safe, effective and economical agent to alleviate inflammatory conditions is still elusive.

Prof. Dr. Jane McHowat
Guest Editor

Submission

All manuscripts should be submitted to pharmaceuticals@mdpi.org with a copy to the Guest Editor. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed Open Access monthly journal published by MDPI.

• inflammation
• arachidonic acid
• prostaglandins
• leukotrienes
• phospholipase A2

Manuscript ID: Pharmaceuticals-NSAID-20091113- Burnett-us
Type of Paper: Review
Title: Exacerbation of NSAID-Induced Injury: A 5-Lipoxygenase Mediated Phenomenon
Authors: Bruce P. Burnett and Robert M. Levy
Affiliation: Primus Pharmaceuticals, Inc. 4725 N. Scottsdale Road, Suite 200, Scottsdale, AZ 85251, USA; E-Mails: bburnett@primusrx.com, rlevy@primusrx.com
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs), both cyclooxygenase-1 (COX-1) and COX-2 inhibitors, produce characteristic side effects. Greater inhibition of COX-1 results in increased gastric toxicity while selective COX-2 inhibition gives predominantly edema, hypertension and cardiovascular side effects. Both types of this heterogeneous anti-inflammatory class carry "black box" warnings for both gastrointestinal (GI) and cardiovascular adverse events. Many of the side effects are the result of arachidonic acid (AA) metabolism imbalances due to targeted enzymatic inihibition. For example, COX-1 inhibition reduces protective prostaglandins in the stomach contributing to GI ulceration and thromboxanes from platelets leading to increased blood thinning. Thromboxanes, in addition to their activating function for platelet aggregation, cause vasoconstriction of arteries and arterioles. Alternatively, COX-2 inhibiters down-regulate inducible prostaglandin and prostacyclin production. Vasodilatory prostacyclins serve to counteract the effects of thromboxanes. Reduction of prostacyclins by COX-2 inhibition leads to increased thromboxane-mediated vasoconstriction resulting in decreased urine production, fluid retention, edema and hypertension which can lead to myocardial infarction and stroke. Inhibition of COX-1 and/or COX-2 "shunts" AA metabolism down the 5-lipoxygenase (5-LOX) pathway to produce potent chemoattractive and vasoconstrictive leukotrienes. This review focuses on the contribution of the 5-LOX shunt in leukotriene production which exacerbates the inherent side effects of NSAIDs and suggests that this metabolic pathway should also be considered as a target for inhibition in anti-inflammatory therapy.

Manuscript ID: Pharmaceuticals- NSAID-20091116- Fujimori-jp
Type of Paper: Review
Title: A Review of NSAIDs-Induced Gastrointestinal Injury: Focused on Prevention for Small-Intestinal Injury
Authors: Shunji Fujimori et al.
Affiliations: Department of Internal Medicine, Division of Gastroenterology, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan; E-Mail: s-fujimori@nms.ac.jp
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious upper gastrointestinal side effects including ulceration. Until recently, most studies on NSAID-associated injury have focused on the upper gastrointestinal tract. However, epidemiological studies suggest that NSAIDs may also increase the risk for lower gastrointestinal adverse events. Capsule endoscopy and double-balloon endoscopy, advanced modalities that now allow for full investigation of the entire small-intestine, have revealed that NSAIDs can cause a variety of abnormalities in the small-intestine; such as ulcerations, perforation, bleeding and diaphragm-like stricture. Recently, the several protective measures against the small-intestinal risk posed by NSAIDs have been evaluated.

Manuscript ID: Pharmaceuticals-NSAID-20091117-De Cosmo-it
Type of Paper: Review
Title: Role of Conventional Nonsteroidal Anti-Inflammatory Drugs and
Cyclo-Oxygenase-2-Specific Inhibitors in the Treatment of Postoperative
Pain
Authors: Germano De Cosmo; E-Mail: gdecosmo@rm.unicatt.it
Abstract: Adequate management of postoperative pain is crucial not only for the best patient comfort and satisfaction but also to improve patient recovery, provide an early mobilization and reduce the length of hospital stay. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used alone for the treatment of mild to moderate pain associated with minor surgical procedures, and as part of a multimodal therapy for pain associated to major surgical procedures. However, in recent years in order to avoid side effects of conventional NSAIDs, new drugs with selective inhibition of cyclo-oxygenase-2 (COX 2) have been introduced. The purpose of this paper is to critically review the most recent literature regarding the use of the conventional NSAIDs and COX2 inhibitors in the treatment of acute postoperative pain.

Manuscript ID: Molecules-NSAID-20091120-Reese-us
Type of Paper: Review
Title: The Role of Non-Steroidal Anti-Inflammatory Drugs in Modulating Prostate Carcinogenesis and Disease Recurrence
Authors: Adam C. Reese and John S. Witte
Affiliation: Department of Urology, University of California, San Francisco, USA; E-Mail: AReese@urology.ucsf.edu; wittej@humgen.ucsf.edu
Abstract: Increasing evidence suggests that prostatic inflammation plays key role in the development of prostate cancer. Despite conflicting results from epidemiological studies, it appears that non-steroidal anti inflammatory drugs (NSAIDs) may reduce the risk of prostate cancer through their anti-inflammatory effects. Preliminary evidence suggests that this protective effect is modulated by genetic variation in cyclooxygenase-2, lymphotoxin alpha (LTA), and other proteins involved in the inflammatory response.
Although the literature is sparse regarding the role of inflammation in predicting outcome after definitive treatment, NSAID use may also alter the risk of prostate cancer recurrence after surgery or radiation therapy. This potential association deserves further investigation, as it may assist in pre-treatment risk stratification.

Manuscript ID: Pharmaceuticals-NSAID-20091123-Bilhim-pt
Type of Paper: Review
Title: Role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in the Management of the Post-Embolization Symptoms after Uterine Artery Embolization.
Authors: Tiago Bilhim and João Martins Pisco; E-Mails: tiagobilhim@hotmail.com; Joao.Pisco@hpv.min-saude.pt; joaopisco.rad@fcm.unl.pt; joao.pisco@chln.min-saude.pt
Abstract: Uterine artery embolization (UAE) is usually a very painful procedure. Although pain after the procedure can occur as a single symptom, it usually is associated with other symptoms such as nausea, vomiting, pelvic pain, general malaise, fever and leukocytosis that characterize the post-embolization syndrome. Management of the post-embolization symptoms and of pain in particular, is paramount if UAE is to be performed as an outpatient procedure. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in association with analgesic drugs to control post-embolization symptoms with many different protocols. In our institution the patients start oral medication with NSAIDs the day before the procedure and continue it during and after UAE. Also we mix NSAIDs with the embolizing particles. This enables a reduction in the inflammation present in the uterine fibroids and helps controlling the pain. The purpose of this paper is to review the importance of NSAIDs in the management of the post-embolization symptoms. We describe the protocol that we use in our institution that enables us to perform the procedure on an outpatient basis with same day discharge and good control of the post-embolization symptoms with oral NSAIDs and analgesics.

Manuscript ID: Pharmaceuticals-NSAID-20091124-Tabuchi-jp
Type of Paper: Review
Title: Effects of NSAIDs on the Inner Ear: Possible Involvement in Cochlear Protection
Authors: Tomofumi Hoshino, Keiji Tabuchi and Akira Hara; E-Mail: ktabuchi@md.tsukuba.ac.jp
Abstract: Cyclooxygenase and lipoxygenase, two important enzymes involved in arachidonic acid metabolism, are major targets of nonsteroidal anti-inflammatory drugs (NSAIDs). The recent investigations suggest that arachidonic cascades and their metabolites may be involved in maintaining inner ear functions. Excessive use of aspirin may cause a tinnitus in human and impairment of outer hair cell functions in experimental animals. On the other hand, NSAIDs reportedly exhibits protective effects on various kinds of inner ear disorders. The present review summarizes the effects of NSAIDs on cochlear pathophysiology. NSAIDs will be a useful ameliorative adjunct in the management of inner ear disorders.

Manuscript ID: Pharmaceuticals-NSAID-20091124-Kotake-jp
Type of Paper: Review
Title: The effect of NSAIDs on the Differentiation and the Function of Osteoclasts
Author: Shigeru Kotake; E-Mail: skotake@ior.twmu.ac.jp
Abstract: Osteoclasts play a critical role in both the normal bone metabolism and the bone resorption in the joints of patients with rheumatoid arthritis. It has been reported that NSAIDs inhibits the osteoclastogenesis in vitro, but not in the joints of patients with rheumatoid arthritis. In the current review article, we review the recent findings in the effect of NSAIDs on the osteoclastogenesis both in vitro and in vivo.

Manuscript ID: Pharmaceuticals-nsaid-20091128-Suzuki-jp
Type of Paper: Review
Title: NSAIDs and Mitochondria and Calcium Signaling
Author: Yoshihiro Suzuki; E-Mail: suzuki.yosihiro@silver.plala.or.jp
Abstract: Aspirin (acetylsalicylic acid, ASA) is a well-known nonsteroidal anti-inflammatory drug (NSAIDs) that can potentiate some acute allergies and causes adverse immunological reactions collectively referred to as aspirin intolerance: a disorder that induces urticaria, asthma and anaphylaxis in response to oral administration of the drug. ASA and NSAIDs have been shown to exhibit chemopreventive effect on cancer and induce cell death by apoptosis in tumor cells. It becomes increasingly evident that ASA and its metabolite salicylic acid target mitochondria and Ca²⁺ signaling pathway. In this review, we overview our current knowledge on the roles of mitochondria and Ca²⁺ homeostasis in the immunomodulatory and tumor killing effects of ASA and NSAIDs, putting on a special interest in the emerging role of L-type Ca²⁺ channels, a new Ca²⁺ entry pathway in non-excitable cells including tumor cells.

Manuscript ID: Pharmacetitcals-NSAID-20091203-Wex-de
Type of Paper: Review
Title: Nonsteroidal Anti-Inflammatory Drug-Induced Gastroduodenal Bleeding: Risk Factors and Prevention Strategies
Author: Thomas Wex
Abstract: Summary. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely prescribed medications in the world. A frequent complication of NSAID-use is gastroduodenal bleeding. Risk factors for gastroduodenal bleeding while on NSAID therapy are older age, prior peptic ulcer and co-medication with anti-platelet agents, anticoagulants, glucocorticoids and selective serotonin-reuptake inhibitors (SSRI). Prevention strategies for at-risk patients include the use of the lowest effective dose of NSAIDs, co-therapy with proton-pump inhibitors and/or the use of a COX-2 selective agent. Treatment of Helicobacter pylori infection is beneficial for primary prophylaxis of NSAID-induced gastroduodenal bleeding. For patients with cardiovascular risk factors requiring NSAIDs, naproxen should be selected. In very high risk patients for both gastrointestinal and cardiovascular complications NSAID therapy should be avoided.
Keywords: NSAIDs; gastroduodenal bleeding; risk factors; prevention strategies

Manuscript ID: Pharmaceuticals-NSAIDs-20091505-Rao-Ca
Type of Paper: Review
Title: Nonsteroidal Anti-inflammatory Drugs (NSAIDs): Progress in Small Molecule Drug Development
Authors: Praveen P. N. Rao
Affiliation: School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, ON, N2G 1C5, Canada; Email: praopera@uwaterloo.ca
Abstract: Ever since the discovery of aspirin, small molecule therapeutics is widely prescribed to treat inflammation and pain. Aspirin and several small molecule NSAIDs are known to inhibit the enzymes cyclooxygenases-1 and -2. Despite the success of NSAIDs to treat inflammatory disorders, the development of a clinically useful small molecule NSAID with decreased side effect profile is an ongoing effort. The recent discovery and development of selective COX-2 inhibitors was a step toward this direction. Emerging trends are represented by the progress in the development of hybrid agents such as nitric oxide donor-NSAIDs (NO-NSAIDs) and dual cyclooxygenase/lipoxygenase inhibitors. This review focuses on the recent advances in the rational design of small molecule NSAIDs in therapy.

Type of Paper: Review
Title: A Comprehensive Review of Injectable Non-steroidal Anti-inflammatory Drugs: Where Are We in 2010?
Authors: Mary Gauthier-Lewis, Conchetta White-Fulton and Treavor Riley
Affiliation: ULM College of Pharmacy, Baton Rouge Campus, Pharmacy Practice, (Critical Care) , LSU Health Sciences Center, Earl K Long Medical Center 3849, North Blvd (Room 218) Baton Rouge, Louisiana 70806, USA; E-Mail: mlewis7@lsuhsc.edu
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) remain one of the most frequently prescribed classes of medications despite their gastrointestinal, renal, cerebrovascular, and cardiovascular risks. These pharmacological agents are used primarily for their anti-inflammatory, antipyretic, and analgesic properties. NSAIDs exhibit these effects via inhibition of cyclocoxygenases (COXs). Selecting an appropriate NSAID for subsets of patients is an ongoing challenge for clinicians despite the availability of guidelines. The emphasis of this article is to comprehensively review the literature for presenting evidence for the injectable acetic acid derivative NSAIDs ((Ibuprofen and Ketorolac) with a focus on risks versus benefits secondary to adverse events.

Type of Paper: Review
Title: What Have We Learned about Neuroinflammation in Neurological Dysfunction?
Authors: Amy H. Moore et al.
Affiliation: Department of Biology, Carleton College, One North College Street, Northfield, MN 55057, USA; E-Mail: amoore@carleton.edu
Abstract: Inflammation is a common component of neurological disease and disorder. Increasing attention has been devoted to understanding the benefits and costs of the innate neuroinflammatory response to functional recovery following brain insult or pathology onset. This review will provide an update on the efficacy of non-steroidal anti-inflammatory drug (NSAID) treatment in recent clinical trials and experimental animal models of neurodegenerative disease. Particular focus will be devoted to the impact of NSAIDs on cognitive performance, highlighting the contribution of neuroinflammatory-related molecules to normal mnemonic processes.

Type of Paper: Article
Title: In Silico Screening of NSAID Effects and Their Combination Actions on COX-1,2
Authors: A. Goltsov ^1,2, G. Lebedeva ³, I. Humphery-Smith ⁴, Y. Kosinsky ⁵, O. Demin ⁵ and I. Goryanin ^2,6
Affiliations: ¹ The University of Abertay Dundee, Dundee, UK
² Centre for Research in Informatics and Systems Pathology, University of Edinburgh, Edinburgh, UK
³ Centre for Systems Biology at Edinburgh, University of Edinburgh, Scotland, UK
⁴ Deomed, Newcastle upon Tyne, UK
⁵ A.N. Belozersky Institute of Physico-Chemical Biology, Moscow State University, Russia
⁶ School of Informatics, University of Edinburgh, UK; E-Mail: alexey.goltsov@googlemail.com
Abstract: The detailed kinetic model of cyclooxygenase-1,2 (COX-1,2) was applied to in silico screening of dose-dependences for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs) such as reversible/irreversible, nonselective/selective to COX-1/COX-2, time dependent/independent inhibitors (aspirin, naproxen, indomethacin, ibuprofen, celecoxib, rofecoxib, etc.)
The computational screening has shown a significant variability in drug IC₅₀ and COX-1/COX-2 selectivity of the same drug depending on different in vitro and in vivo experimental conditions. To study high heterogeneity in the inhibition effect of NSAIDs, we have developed an in silico approach to evaluate NSAID action on target under different microenvironmental conditions of COX-1,2, such as arachidonic acid activation level, reducing cofactor concentration, peroxide level, and the ratio of COX-1/COX-2 expression status in the experimental assay. The designed technique permits translating IC₅₀ and COX-1/COX-2 selectivity, obtained in one experimental setting to another, and predicts in vivo inhibitory effects basing on relevant in vitro data. For aspirin we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficasy, depending on COX-1,2 microenvironment in in vitro/in vivo experimental settings.
Also we presents the results of the in silico screening of the combined action of two NSAIDs (e.g. aspitin, indomethacin +celecoxib, ibuprofen, Vioxx, etc), which presents a more complex and controversial effect of NSAIDs. We show that the experimentally observed effect of suppression of aspirin-mediated COX-1 inhibition by selective and nonselective NSAIDs is extremely sensitive to COX-1,2 microenvironment in in vivo experiments. Also the antagonism effect of two NSAIDs was found to depend on the type of NSAIDs in combination.
We discuss the application of the obtained results to the problems of standardisation of NSAID test assay, dependence of the NSAID efficacy on COX-1,2 cellular environment, drug resistance, and combination therapy.

Type of Paper: Review
Title: Cancer Chemopreventive Properties of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Is Cyclooxygenase Inhibition Necessary?
Author: Gary A. Piazza; E-Mail: piazza@southernresearch.org
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) display striking antineoplastic activity, but toxicity from cyclooxygenase (COX) inhibition and incomplete protection from disease progression limits their use for cancer chemoprevention. Previous studies suggest that the mechanism for the chemopreventive activity of certain NSAIDs (e.g. sulindac), does not require the inhibition of COX-1 or -2, but instead involves cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) inhibition. Therefore, it may be feasible to discover new drugs for cancer chemoprevention that are safer and more efficacious than currently available NSAIDs and COX-2 selective inhibitors by targeting cGMP PDE. Such drugs would be especially useful for patients who are at high risk of malignant progression.

Type of Paper: Review
Title: Critical Overview on the Benefits and Harms of Aspirin
Authors: Y.K. Loke and C.S. Kwok
Affiliation: University of East Anglia, Norwich, UK; E-Mail: Y.Loke@uea.ac.uk
Abstract: Aspirin is widely used internationally for a variety of indications, with the most prominent one being that of cardiovascular disease. However, aspirin has also been proposed as a treatment option in a diverse range of conditions such as atrial fibrillation, venous thromboembolism, cancer prevention, and prophylaxis of miscarriages in susceptible women. In our overview, we critically appraise the current evidence from existing systematic reviews and meta-analyses covering the benefits of aspirin across these conditions. Aspirin is also associated with the potential for significant harm, principally from peptic ulcer and haemorrhagic adverse events. We critically appraise the threat of gastrointestinal complications and cerebral haemorrhage, and weigh up these risks against that of any potential benefit.

Type of Paper: Review

Title: Non-steroidal Anti-Inflammatory Drugs: Overview of Cardiovascular Risks
Authors: Harald Vonkeman et al. 

Affiliation: Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente and University of Twente, Ariensplein 1, 7500 KA Enschede, The Netherlands; E-Mail: h.vonkeman@mst.nl

Abstract: While aspirin may offer protection, other non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) can cause serious cardiovascular side effects and complications. This has led to a general "black box" warning for cardiovascular adverse events for NSAIDs. This review explores the different mechanisms underlying the protective effects of aspirin, the NSAID associated renovascular effects causing hypertension, edema and heart failure, the cardiovascular effects causing myocardial infarction and stroke, and the possible deleterious interaction between NSAIDs and Aspirin.

Title: Exacerbation of NSAID induced injury: A 5-lipoxygenase mediated phenomenon
Authors: Bruce P. Burnett, Lakshmi Pillai, Robert M. Levy; E-Mail: bburnett@primusrx.com (B.P.B.)
Abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs), both cyclooxygenase-1 (COX-1) and COX-2 inhibitors, produce characteristic side effects. Greater inhibition of COX-1 results in increased gastric toxicity while selective COX-2 inhibition gives predominantly edema, hypertension and cardiovascular side effects. Both types of this heterogeneous anti-inflammatory class carry black box warnings for both gastrointestinal (GI) and cardiovascular adverse events. Much of the side effects are mediated by imbalances in arachidonic acid (AA) metabolites. For example, COX-1 inhibition reduces protective prostaglandins in the stomach contributing to GI ulceration and thromboxanes from platelets leading to increased blood thinning. Thromboxanes, in addition to their activating function for platelet aggregation, cause vasoconstriction of arteries and arterioles. Alternatively, COX-2 inhibiters down-regulate inducible prostaglandin and prostacyclin production. Vasodilatory prostacyclins serve to counteract the effects of thromboxanes. Reduction of prostacyclins by COX-2 inhibition leads to increased vasoconstriction resulting in decreased urine production, fluid retention, edema, hypertension which may lead to myocardial infarction and stroke. Inhibition of COX-1 and COX-2 also “shunts” AA metabolism down the 5-lipoxygenase (5-LOX) pathway to produce potent chemoattractive and vasoconstrictive leukotrienes. This review focuses on the contribution of the 5-LOX shunt in leukotriene production which exacerbates the inherent side effects of NSAIDs and suggests that this metabolic pathway should also be considered as a target for inhibition in anti-inflammatory therapy.

Type of Paper: Review
Title: Central Nervous System Actions of NSAIDs
Authors: Parto S Khansari, Leanne Coyne and Robert F Halliwell
Affiliation: California Northstate College of Pharmacy, Rancho Cordova, CA, USA
Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA, USA; E-Mail: rhalliwell@PACIFIC.EDU (F.H.)
Abstract: Inhibition of cyclooxygenase (COX) isoenzymes is the primary effect of non-steroidal anti-inflammatory drugs (NSAID’s) in the human body and the reason for their extensive use in the treatment of pain and inflammatory disorders. However, NSAID’s are a diverse group of agents with some possessing unique pharmacological properties in addition to COX inhibition. Recent data indicate that COX and non-COX actions may contribute to the efficacy of NSAID’s in the treatment of several neurological diseases including stroke, Alzheimer’s disease, Amyotrophic Lateral Sclerosis, Parkinson’s disease, and epilepsy. The purpose of this review is to explore the pharmacology of NSAID’s in relation to their current uses and their potential value in the treatment of neurological conditions in the future.

Title: The Role of Non-Steroidal Anti-Inflammatory Drugs in Renal Colic
Authors: Kim Davenport and Elizabeth Waine
Affiliation: Bristol Urological Institute, Southmead Hospital, Bristol, BS10 5NB, UK; E-Mail: DrKimDav@aol.com
Abstract: NSAIDs provide optimal analgesia in renal colic owing to the reduction in glomerular filtration and renal pelvic pressure, ureteric peristalsis and ureteric oedema. Prevention of glomerular afferent arteriolar vasodilatation renders these patients at risk of renal impairment. NSAIDs have the additional benefit of reducing the number of new colic episodes and preventing subsequent readmission to hospital. Despite recent work promoting the use of pharmacological agents to improve stone passage rates, NSAIDs do not appear to reduce the time to stone passage or increase the likelihood of stone passage in renal colic.