Pharmacotherapy Commentary| Volume 34, ISSUE 9, P1954-1963, September 2012

Need to Develop New Nonsteroidal Anti-Inflammatory Drug Formulations

Published:September 03, 2012DOI:



      In the management of pain, primary care physicians are often the first to diagnose and treat acute or chronic painful conditions. This places them in an important intersection to manage pain, in which safe and effective therapeutic options are paramount for their patients. For decades, NSAIDs have been routinely prescribed for relief of mild to moderate acute and chronic pain. Yet, safety and tolerability concerns associated with the use of this class of drugs continue to be an issue for patients and clinicians.


      The objective of this review was to discuss the unmet medical needs of patients in the management of pain and inflammation, review the dose-dependent safety data associated with use of NSAIDs, and discuss the need to develop new NSAID formulations to improve safety and tolerability while maintaining efficacy.


      We performed literature searches of the PubMed and Cochrane Library databases through December 2012 for articles in English that reported dose-dependent safety and tolerability data associated with use of NSAIDs.


      The risk of serious, dose-dependent adverse events involving the gastrointestinal tract, cardiovascular system, and kidneys is associated with use of NSAIDs. On the basis of these findings, the US Food and Drug Administration has requested that the package insert for all NSAIDs be revised to include a boxed warning highlighting the potential increased risk of cardiovascular events and the risk of serious, and potentially life-threatening, gastrointestinal tract bleeding. While using lower dosages of a particular NSAID may be associated with lower rates of adverse events, maintaining the clinical efficacy of standard NSAID dosages remains a challenge.


      There is a need to develop new and effective NSAID formulations to minimize the safety and tolerability concerns associated with currently available NSAIDs, yet maintain efficacy in management of inflammation and pain.

      Key words

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      1. Indomethacin [prescribing information].
        Heritage Pharmaceuticals, Inc, Edison, NJ2010
      2. Naproxen [prescribing information].
        Roxane Laboratories, Inc, Columbus, OH2010
      3. Voltaren [prescribing information].
        Novarttis Pharmaceuticals Corp, East Hanover, NJ2011
        • Hart F.D.
        • Boardman P.L.
        Indomethacin: a new non-steroid anti-inflammatory agent.
        Br Med J. 1963; 2: 965-970
        • Ong C.K.
        • Lirk P.
        • Tan C.H.
        • Seymour R.A.
        An evidence-based update on nonsteroidal anti-inflammatory drugs.
        Clin Med Res. 2007; 5: 19-34
        • Wallace J.L.
        • Granger D.N.
        The cellular and molecular basis of gastric mucosal defense.
        FASEB J. 1996; 10: 731-740
        • Wallace J.L.
        Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself?.
        Physiol Rev. 2008; 88: 1547-1565
        • IMS Institute for Healthcare Informatics
        NSAID Prescriptions in the United States.
        IMS, Parsippany, NJ2011
        • US Food and Drug Administration
        Public Health Advisory: FDA announces important changes and additional warnings for COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs).
        (Accessed January 15, 2011)
        • Haanpaa M.L.
        • Backonja M.M.
        • Bennett M.I.
        • et al.
        Assessment of neuropathic pain in primary care.
        Am J Med. 2009; 122: S13-S21
        • Mantyselka P.
        • Kumpusalo E.
        • Ahonen R.
        • et al.
        Pain as a reason to visit the doctor: a study in Finnish primary health care.
        Pain. 2001; 89: 175-180
        • McCarberg B.
        Treatment of mild-to-moderate acute pain: what can we do to improve the standard of care?.
        Am J Ther. 2008; 15: S5-S6
        • Kuehn B.M.
        Opioid prescriptions soar: increase in legitimate use as well as abuse.
        JAMA. 2007; 297: 249-251
        • Walpole M.A.
        Massssachusetts Pain Initiative: Pain Survey Executive Summary.
        • Governdale L.
        Outpatient prescription opioid utilization in the US, years 2000–2009.
        US Food and Drug Administration, Department of Epidemiology, Office of Surveillance and Epidemiology, Silver Spring, MD2010
        • Braden J.B.
        • Fan M.Y.
        • Edlund M.J.
        Trends in use of opioids by noncancer pain type 2000–2005 among Arkansas Medicaid and HealthCore enrollees: results from the TROUP study.
        J Pain. 2008; 9: 1026-1035
        • Caudill-Slosberg M.A.
        • Schwartz L.M.
        • Woloshin S.
        Office visits and analgesic prescriptions for musculoskeletal pain in US: 1980 vs. 2000.
        Pain. 2004; 109: 514-519
        • Sullivan M.D.
        • Edlund M.J.
        • Fan M.Y.
        • et al.
        Trends in use of opioids for non-cancer pain conditions 2000–2005 in commercial and Medicaid insurance plans: the TROUP study.
        Pain. 2008; 138: 440-449
        • Fishbain D.A.
        • Cole B.
        • Lewis J.
        • et al.
        What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors?.
        Pain Med. 2008; 9: 444-459
        • Larson A.M.
        • Polson J.
        • Fontana R.J.
        • et al.
        Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study.
        Hepatology. 2005; 42: 1364-1372
        • Ostapowicz G.
        • Fontana R.J.
        • Schiodt F.V.
        • et al.
        Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States.
        Ann Intern Med. 2002; 137: 947-954
      4. A call to revolutionize chronic pain care in America an opportunity in health care reform [amended March 4, 2010].
        Mayday Fund, New York, NY2009
        • McLean S.A.
        • Clauw D.J.
        • Abelson J.L.
        • Liberzon I.
        The development of persistent pain and psychological morbidity after motor vehicle collision: integrating the potential role of stress response systems into a biopsychosocial model.
        Psychosom Med. 2005; 67: 783-790
      5. American Pain Society Clinical Practice Guidelines.
        (Accessed May 2, 2012)
        • American Academy of Pain Medicine
        (Accessed May 2, 2012)
        • García Rodríiguez L.A.
        • Jick H.
        Risk of upper gastrointestinal bleeding and perforation associated with individual non-steroidal anti-inflammatory drugs.
        Lancet. 1994; 343: 769-772
        • Harris M.D.
        • Siegel L.B.
        • Alloway J.A.
        Gout and hyperuricemia.
        Am Fam Physician. 1999; 59: 925-934
        • Singh G.
        • Rosen Ramey D.
        NSAID induced gastrointestinal complications: the ARAMIS perspective, 1997: Arthritis, Rheumatism, and Aging Medical Information System.
        J Rheumatol Suppl. 1998; 51: 8-16
        • Borer J.S.
        • Simon L.S.
        Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance.
        Arthritis Res Ther. 2005; 7: S14-S22
        • Boardman P.L.
        • Hart F.D.
        Side-effects of indomethacin.
        Ann Rheum Dis. 1967; 26: 127-132
        • Lewis S.C.
        • Langman M.J.
        • Laporte J.R.
        • et al.
        Dose-response relationships between individual nonaspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta-analysis based on individual patient data.
        Br J Clin Pharmacol. 2002; 54: 320-326
        • García Rodríguez L.A.
        • Hernandez-Diaz S.
        Risk of uncomplicated peptic ulcer among users of aspirin and nonaspirin nonsteroidal antiinflammatory drugs.
        Am J Epidemiol. 2004; 159: 23-31
        • Laporte J.R.
        • Ibanez L.
        • Vidal X.
        • et al.
        Upper gastrointestinal bleeding associated with the use of NSAIDs: newer versus older agents.
        Drug Safety. 2004; 27: 411-420
        • García Rodríguez L.A.
        • Cattaruzzi C.
        • Troncon M.G.
        • Agostinis L.
        Risk of hospitalization for upper gastrointestinal tract bleeding associated with ketorolac, other nonsteroidal anti-inflammatory drugs, calcium antagonists, and other antihypertensive drugs.
        Arch Intern Med. 1998; 158: 33-39
        • García Rodríguez L.A.
        • Barreales Tolosa L.
        Risk of upper gastrointestinal complications among users of traditional NSAIDs and COXIBs in the general population.
        Gastroenterology. 2007; 132: 498-506
        • Lanas A.
        • García-Rodríguez L.A.
        • Arroyo M.T.
        • et al.
        • Associón Española de Gastroenterología
        Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase-2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations.
        Gut. 2006; 55: 1731-1738
        • Langman M.J.
        • Weil J.
        • Wainwright P.
        • et al.
        Risks of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs.
        Lancet. 1994; 343: 1075-1078
        • Bueno H.
        • Bardaji A.
        • Patrignani P.
        • et al.
        Use of non-steroidal antiinflammatory drugs and type-specific risk of acute coronary syndrome.
        Am J Cardiol. 2010; 105: 1102-1106
        • Fosbol E.L.
        • Folke F.
        • Jacobsen S.
        • et al.
        Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals.
        Circ Cardiovasc Quality Outcomes. 2010; 3: 395-405
        • Fosbol E.L.
        • Gislason G.H.
        • Jacobsen S.
        • et al.
        Risk of myocardial infarction and death associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) among healthy individuals: a nationwide cohort study.
        Clin Pharmacol Ther. 2009; 85: 190-197
        • García Rodríguez L.A.
        • Tacconelli S.
        • Patrignani P.
        Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population.
        J Am Coll Cardiol. 2008; 52: 1628-1636
        • Gislason G.H.
        • Jacobsen S.
        • Rasmussen J.N.
        • et al.
        Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.
        Circulation. 2006; 113: 2906-2913
        • Biskupiak J.E.
        • Brixner D.I.
        • Howard K.
        • Oderda G.M.
        Gastrointestinal complications of over-the-counter nonsteroidal antiinflammatory drugs.
        J Pain Palliat Care Pharmacother. 2006; 20: 7-14
        • Blot W.J.
        • McLaughlin J.K.
        Over the counter non-steroidal anti-inflammatory drugs and risk of gastrointestinal bleeding.
        J Epidemiol Biostat. 2000; 5: 137-142
        • Griffin M.R.
        • Piper J.M.
        • Daugherty J.R.
        • et al.
        Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons.
        Ann Intern Med. 1991; 114: 257-263
        • Mellemkjaer L.
        • Blot W.J.
        • Sorensen H.T.
        • et al.
        Upper gastrointestinal bleeding among users of NSAIDs: a population-based cohort study in Denmark.
        Br J Clin Pharmacol. 2002; 53: 173-181
        • Wang J.
        • Donnan P.T.
        • MacDonald T.M.
        An approximate Bayesian risk-analysis for the gastro-intestinal safety of ibuprofen.
        Pharmacoepidemiol Drug Safety. 2002; 11: 695-701
        • Bombardier C.
        • Laine L.
        • Reicin A.
        • et al.
        • VIGOR Study Group
        Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis.
        N Engl J Med. 2000; 343 (2 p following 1528): 1520-1528
        • Ott E.
        • Nussmeier N.A.
        • Duke P.C.
        • et al.
        Efficacy and safety of the cyclooxygenase 2 inhibitors parecoxib and valdecoxib in patients undergoing coronary artery bypass surgery.
        J Thorac Cardiovasc Surg. 2003; 125: 1481-1492
        • Bresalier R.S.
        • Sandler R.S.
        • Quan H.
        • et al.
        Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial.
        N Engl J Med. 2005; 352: 1092-1102
        • Nussmeier N.A.
        • Whelton A.A.
        • Brown M.T.
        • et al.
        Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery.
        N Engl J Med. 2005; 352: 1081-1091
        • Solomon S.D.
        • McMurray J.J.
        • Pfeffer M.A.
        • et al.
        Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention.
        N Engl J Med. 2005; 352: 1071-1080
        • Schmidt M.
        • Christiansen C.F.
        • Mehnert F.
        • et al.
        Non-steroidal anti-inflammatory drug use and risk of atrial fibrillation or flutter: population based case-control study.
        BMJ. 2011; 343: d3450
        • Graham D.J.
        • Campen D.
        • Hui R.
        • et al.
        Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study.
        Lancet. 2005; 365: 475-481
        • McGettigan P.
        • Henry D.
        Cardiovascular risk with non-steroidal anti-inflammatory drugs: systematic review of population-based controlled observational studies.
        PLoS Med. 2011; 8
        • Whelton A.
        Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications.
        Am J Med. 1999; 106: 13S-24S
        • Gooch K.
        • Culleton B.F.
        • Manns B.J.
        • et al.
        NSAID use and progression of chronic kidney disease.
        Am J Med. 2007; 120: 280.e281-280.e287
        • Griffin M.R.
        • Yared A.
        • Ray W.A.
        Nonsteroidal antiinflammatory drugs and acute renal failure in elderly persons.
        Am J Epidemiol. 2000; 151: 488-496
        • Henry D.
        • Page J.
        • Whyte I.
        • et al.
        Consumption of non-steroidal anti-inflammatory drugs and the development of functional renal impairment in elderly subjects: results of a case-control study.
        Br J Clin Pharmacol. 1997; 44: 85-90
        • Huerta C.
        • Castellsague J.
        • Varas-Lorenzo C.
        • Garcia Rodriguez L.A.
        Nonsteroidal anti-inflammatory drugs and risk of ARF in the general population.
        Am J Kidney Dis. 2005; 45: 531-539
        • Kuo H.W.
        • Tsai S.S.
        • Tiao M.M.
        • et al.
        Analgesic use and the risk for progression of chronic kidney disease.
        Pharmacoepidemiol Drug Safety. 2010; 19: 745-751
        • Perez Gutthann S.
        • Garcia Rodriguez L.
        • Raiford D.
        • et al.
        Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for acute renal failure.
        Arch Intern Med. 1996; 156: 2433-2439
        • Schneider V.
        • Levesque L.E.
        • Zhang B.
        • Hutchinson T.
        • Brophy J.M.
        Association of selective and conventional nonsteroidal antiinflammatory drugs with acute renal failure: a population-based, nested case-control analysis.
        Am J Epidemiol. 2006; 164: 881-889
        • Giagoudakis G.
        • Markantonis S.L.
        Relationships between the concentrations of prostaglandins and the nonsteroidal antiinflammatory drugs indomethacin, diclofenac, and ibuprofen.
        Pharmacotherapy. 2005; 25: 18-25
        • Rane A.
        • Oelz O.
        • Frolich J.C.
        • et al.
        Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man.
        Clin Pharmacol Ther. 1978; 23: 658-668
        • Ekstrand R.
        • Alván G.
        • L'e Orme M.
        • et al.
        Double-blind dose-response study of indomethacin in rheumatoid arthritis.
        Eur J Clin Pharmacol. 1980; 17: 437-442
        • Dunagan F.M.
        • McGill P.E.
        • Kelman A.W.
        • Whiting B.
        Naproxen dose and concentration: response relationship in rheumatoid arthritis.
        Br J Rheumatol. 1988; 27: 48-53
        • Derry C.
        • Derry S.
        • Moore R.A.
        • McQuay H.J.
        Single dose oral naproxen and naproxen sodium for acute postoperative pain in adults.
        Cochrane Database Syst Rev. 2009; (CD004234)
        • Kubitzek F.
        • Ziegler G.
        • Gold M.S.
        • et al.
        Low-dose diclofenac potassium in the treatment of episodic tension-type headache.
        Eur J Pain. 2003; 7: 155-162
        • Gehanno P.
        • Dreiser R.L.
        • Ionescu E.
        • et al.
        Lowest effective single dose of diclofenac for antipyretic and analgesic effects in acute febrile sore throat.
        Clin Drug Invest. 2003; 23: 263-271
        • Schachtel B.P.
        • McCabe D.
        • Berger M.
        • et al.
        Efficacy of low-dose celecoxib in patients with acute pain.
        J Pain. 2011; 12: 756-763
        • Zhang W.
        • Nuki G.
        • Moskowitz R.W.
        • et al.
        OARSI recommendations for the management of hip and knee osteoarthritis.
        Osteoarthritis Cartilage. 2010; 18: 476-499