• 1
    Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, et al. OARSI recommendations for the management of hip and knee osteoarthritis, part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16: 13762.
  • 2
    Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev 2006; 1:CD004257.
  • 3
    Apkarian AV, Baliki MN, Geha PY. Towards a theory of chronic pain. Prog Neurobiol 2009; 87: 8197.
  • 4
    Schaible HG, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann N Y Acad Sci 2002; 966: 34354.
  • 5
    Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal anti-inflammatory drugs: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1995; 123: 2419.
  • 6
    Rostom A, Muir K, Dube C, Jolicoeur E, Boucher M, Joyce J, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol 2007; 5: 81828.
  • 7
    Farkouh ME, Greenberg BP. An evidence-based review of the cardiovascular risks of nonsteroidal anti-inflammatory drugs. Am J Cardiol 2009; 103: 122737.
  • 8
    Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332: 13028.
  • 9
    Lester G. Clinical research in OA: the NIH Osteoarthritis Initiative. J Musculoskelet Neuronal Interact 2008; 8: 3134.
  • 10
    Hunter DJ, Hellio Le Graverand-Gastineau MP. How close are we to having structure-modifying drugs available? Med Clin North Am 2009; 93: 22334.
  • 11
    Lo GH, McAlindon TE, Niu J, Zhang Y, Beals C, Dabrowski C, et al. Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2009; 17: 15629.
  • 12
    Pelletier JP, Martel-Pelletier J. DMOAD developments: present and future. Bull NYU Hosp Jt Dis 2007; 65: 2428.
  • 13
    Petruska JC, Mendell LM. The many functions of nerve growth factor: multiple actions on nociceptors. Neurosci Lett 2004; 361: 16871.
  • 14
    Skaper SD. The biology of neurotrophins, signalling pathways, and functional peptide mimetics of neurotrophins and their receptors. CNS Neurol Disord Drug Targets 2008; 7: 4662.
  • 15
    Frade JM, Barde YA. Nerve growth factor: two receptors, multiple functions. Bioessays 1998; 20: 13745.
  • 16
    Lewin GR, Rueff A, Mendell LM. Peripheral and central mechanisms of NGF-induced hyperalgesia. Eur J Neurosci 1994; 6: 190312.
  • 17
    McMahon SB. NGF as a mediator of inflammatory pain. Philos Trans R Soc Lond B Biol Sci 1996; 351: 43140.
  • 18
    Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience 1994; 62: 32731.
  • 19
    Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M. NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 2010; 148: 40713.
  • 20
    Halliday DA, Zettler C, Rush RA, Scicchitano R, McNeil JD. Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease. Neurochem Res 1998; 23: 91922.
  • 21
    Friess H, Zhu ZW, di Mola FF, Kulli C, Graber HU, Andren-Sandberg A, et al. Nerve growth factor and its high-affinity receptor in chronic pancreatitis. Ann Surg 1999; 230: 61524.
  • 22
    Miller LJ, Fischer KA, Goralnick SJ, Litt M, Burleson JA, Albertsen P, et al. Nerve growth factor and chronic prostatitis/chronic pelvic pain syndrome. Urology 2002; 59: 6038.
  • 23
    Jacobs BL, Smaldone MC, Tyagi V, Philips BJ, Jackman SV, Leng WW, et al. Increased nerve growth factor in neurogenic overactive bladder and interstitial cystitis patients. Can J Urol 2010; 17: 498994.
  • 24
    Raychaudhuri SK, Raychaudhuri SP. NGF and its receptor system: a new dimension in the pathogenesis of psoriasis and psoriatic arthritis. Ann N Y Acad Sci 2009; 1173: 4707.
  • 25
    Lane NE, Schnitzer TJ, Smith MD, Brown MT. Efficacy and safety of PF04383119 in treating moderate to severe pain due to osteoarthritis (OA) [abstract]. Ann Rheum Dis 2008; 67 Suppl II: 237.
  • 26
    Lane NE, Schnitzer TJ, Birbara CA, Smith MD, Simpson S, Brown MT, et al. Long-term tanezumab use for treatment of moderate to severe osteoarthritic knee pain: an open-label extension study [abstract]. Arthritis Rheum 2009; 60 Suppl: S312.
  • 27
    National Institutes of Health. Tanezumab search. URL:
  • 28
    Imamura M, Imamura ST, Kaziyama HH, Targino RA, Hsing WT, de Souza LP, et al. Impact of nervous system hyperalgesia on pain, disability, and quality of life in patients with knee osteoarthritis: a controlled analysis. Arthritis Rheum 2008; 59: 142431.
  • 29
    Schaible HG. Spinal mechanisms contributing to joint pain. Novartis Found Symp 2004; 260: 427.
  • 30
    Bradley LA, Kersh BC, DeBerry JJ, Deutsch G, Alarcon GA, McLain DA. Lessons from fibromyalgia: abnormal pain sensitivity in knee osteoarthritis. Novartis Found Symp 2004; 260: 25879.
  • 31
    Kulkarni B, Bentley DE, Elliott R, Julyan PJ, Boger E, Watson A, et al. Arthritic pain is processed in brain areas concerned with emotions and fear. Arthritis Rheum 2007; 56: 134554.
  • 32
    Baliki MN, Geha PY, Jabakhanji R, Harden N, Schnitzer TJ, Apkarian AV. A preliminary fMRI study of analgesic treatment in chronic back pain and knee osteoarthritis. Mol Pain 2008; 4: 47.
  • 33
    Gwilym SE, Keltner JR, Warnaby CE, Carr AJ, Chizh B, Chessell I, et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum 2009; 61: 122634.
  • 34
    Choy EH, Mease PJ, Kajdasz DK, Wohlreich MM, Crits-Christoph P, Walker DJ, et al. Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials. Clin Rheumatol 2009; 28: 103544.
  • 35
    Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol 2008; 8: 29.
  • 36
    Trivedi MH, Desaiah D, Ossanna MJ, Pritchett YL, Brannan SK, Detke MJ. Clinical evidence for serotonin and norepinephrine reuptake inhibition of duloxetine. Int Clin Psychopharmacol 2008; 23: 1619.
  • 37
    Chappell AS, Ossanna MJ, Liu-Seifert H, Iyengar S, Skljarevski V, Li LC, et al. Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: a 13-week, randomized, placebo-controlled trial. Pain 2009; 146: 25360.
  • 38
    Chappell AS, Desaiah D, Liu-Seifert H, Zhang S, Skljarevski V, Belenkov Y, et al. Duloxetine 60–120 mg once daily versus placebo in the treatment of patients with osteoarthritis knee pain [abstract]. Pain Med 2009; 10: S50.
  • 39
    Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. J Rheumatol 2007; 34: 54355.
  • 40
    National Institutes of Health. Duloxetine search. URL:
  • 41
    Moncada S, Palmer RM, Higgs EA. The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 1988; 12: 36572.
  • 42
    Gkaliagkousi E, Douma S, Zamboulis C, Ferro A. Nitric oxide dysfunction in vascular endothelium and platelets: role in essential hypertension. J Hypertens 2009; 27: 231020.
  • 43
    Huang PL. eNOS, metabolic syndrome and cardiovascular disease. Trends Endocrinol Metab 2009; 20: 295302.
  • 44
    Wallace JL, Miller MJ. Nitric oxide in mucosal defense: a little goes a long way. Gastroenterology 2000; 119: 51220.
  • 45
    Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis Res Ther 2008; 10 Suppl 2: S4.
  • 46
    Napoli C, Ignarro LJ. Nitric oxide and pathogenic mechanisms involved in the development of vascular diseases. Arch Pharm Res 2009; 32: 11038.
  • 47
    Wallace JL, Viappiani S, Bolla M. Cyclooxygenase-inhibiting nitric oxide donators for osteoarthritis. Trends Pharmacol Sci 2009; 30: 1127.
  • 48
    Fagerholm U, Bjornsson MA. Clinical pharmacokinetics of the cyclooxygenase inhibiting nitric oxide donator (CINOD) AZD3582. J Pharm Pharmacol 2005; 57: 153954.
  • 49
    Schnitzer TJ, Kivitz A, Frayssinet H, Duquesroix B. Efficacy and safety of naproxcinod in the treatment of patients with osteoarthritis of the knee: a 13-week prospective, randomized, multicenter study. Osteoarthritis Cartilage 2010; 18: 62939.
  • 50
    Marrero CE, Tuten C, Shamin T, Awasty V, Agaiby J, Hassman D, et al. 26-week efficacy and safety evaluation of naproxcinod, a first-in-class cyclooxygenase inhibiting nitric oxide donator (CINOD), in patients with osteoarthritis of the knee [abstract]. Arthritis Rheum 2009; 60 Suppl: S318.
  • 51
    National Institutes of Health. Naproxcinod search. URL:
  • 52
    Wilder-Smith CH, Jonzon B, Fornstedt-Wallin B, Hedman A, Karlsson P. Dose-effect comparisons of the CINOD AZD3582 and naproxen on upper gastrointestinal tract mucosal injury in healthy subjects. Scand J Gastroenterol 2006; 41: 26473.
  • 53
    Hawkey CJ, Jones JI, Atherton CT, Skelly MM, Bebb JR, Fagerholm U, et al. Gastrointestinal safety of AZD3582, a cyclooxygenase inhibiting nitric oxide donator: proof of concept study in humans. Gut 2003; 52: 153742.
  • 54
    Lohmander LS, McKeith D, Svensson O, Malmenas M, Bolin L, Kalla A, et al. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis 2005; 64: 44956.
  • 55
    White WB, Schnitzer TJ, Fleming R, Duquesroix B, Beekman M. Effects of the cyclooxygenase inhibiting nitric oxide donator naproxcinod versus naproxen on systemic blood pressure in patients with osteoarthritis. Am J Cardiol 2009; 104: 8405.
  • 56
    Townsend R, Bittar N, Rosen J, Smith W, Ramsay A, Chrysant S, et al. Differential blood pressure effect of naproxcinod compared with naproxen on ambulatory blood pressure in hypertensive subjects [abstract]. Circulation 2008; 118: S888.
  • 57
    Grover SA, Coupal L, Zowall H. Treating osteoarthritis with cyclooxygenase-2-specific inhibitors: what are the benefits of avoiding blood pressure destabilization? Hypertension 2005; 45: 927.
  • 58
    Lanza FL, Chan FK, Quigley EM. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol 2009; 104: 72838.
  • 59
    Leontiadis GI, Sreedharan A, Dorward S, Barton P, Delaney B, Howden CW, et al. Systematic reviews of the clinical effectiveness and cost-effectiveness of proton pump inhibitors in acute upper gastrointestinal bleeding. Health Technol Assess 2007; 11: 1164.
  • 60
    Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev 2002; 4:CD002296.
  • 61
    Laine L, Connors L, Griffin MR, Curtis SP, Kaur A, Cannon CP. Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines. Aliment Pharmacol Ther 2009; 30: 76774.
  • 62
    National Institutes of Health. PN400 search. URL:
  • 63
    Goldstein J, Hochberg M, Fort J, Crawley J, Sostek M. PN400 significantly improves upper gastrointestinal tolerability compared with enteric-coated naproxen alone in patients requiring chronic NSAID therapy: results from two prospective, randomized, controlled trials [abstract]. Am J Gastroenterol 2009; 104 Suppl 3: S50.
  • 64
    Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Sostek M. PN400 significantly reduces the incidence of gastric ulcers compared with enteric-coated naproxen in patients requiring chronic NSAID therapy regardless of low-dose aspirin use: results from two prospective, randomized controlled trials [abstract]. Arthritis Rheum 2009; 60 Suppl: S314.
  • 65
    Weinblatt ME, Schiff M, Genovese M, Kivitz A, Bello A, Grahn A, et al. Significant reduction in upper gastrointestinal (UGI) ulcers with HZT-501, a single-tablet combination of ibuprofen-famotidine, the REDUCE 1 and 2 trials [abstract]. Ann Rheum Dis 2009; 68 Suppl 3: 704.
  • 66
    Schnitzer TJ, Burmester GR, Mysler E, Hochberg MC, Doherty M, Ehrsam E, et al. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 2004; 364: 66574.
  • 67
    Ali T, Roberts DN, Tierney WM. Long-term safety concerns with proton pump inhibitors. Am J Med 2009; 122: 896903.
  • 68
    Goldring MB, Goldring SR. Osteoarthritis. J Cell Physiol 2007; 213: 62634.
  • 69
    Body JJ. Calcitonin for the long-term prevention and treatment of postmenopausal osteoporosis. Bone 2002; 30 Suppl: 759S.
  • 70
    Karsdal MA, Tanko LB, Riis BJ, Sondergard BC, Henriksen K, Altman RD, et al. Calcitonin is involved in cartilage homeostasis: is calcitonin a treatment for OA? Osteoarthritis Cartilage 2006; 14: 61724.
  • 71
    Karsdal MA, Sondergaard BC, Arnold M, Christiansen C. Calcitonin affects both bone and cartilage: a dual action treatment for osteoarthritis? Ann N Y Acad Sci 2007; 1117: 18195.
  • 72
    Karsdal MA, Byrjalsen I, Henriksen K, Riis BJ, Lau EM, Arnold M, et al. The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study. Osteoarthritis Cartilage 2010; 18: 1509.
  • 73
    Karsdal MA, Henriksen K, Arnold M, Christiansen C. Calcitonin: a drug of the past or for the future? Physiologic inhibition of bone resorption while sustaining osteoclast numbers improves bone quality. BioDrugs 2008; 22: 13744.
  • 74
    National Institutes of Health. Calcitonin search. URL:
  • 75
    Vuolteenaho K, Moilanen T, Knowles RG, Moilanen E. The role of nitric oxide in osteoarthritis. Scand J Rheumatol 2007; 36: 24758.
  • 76
    Abramson SB. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther 2008; 10 Suppl 2: S2.
  • 77
    National Institutes of Health. SD-6010 search. URL: