Dolor crónico OA: Importancia de analgesia multimodal
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Este documento discute la analgesia multimodal en el manejo del dolor. Resume que 1) el dolor crónico requiere un enfoque multimodal que involucre sistemas inhibitorios endógenos como la anandamida, 2) los AINES pueden usarse como parte de la analgesia multimodal pero requieren precauciones debido a los riesgos gastrointestinales y cardiovasculares, especialmente en pacientes con múltiples factores de riesgo, y 3) la sinergia entre analgésicos con diferentes mecanismos de acción puede reducir los efectos adversos y
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Dolor crónico OA: Importancia de analgesia multimodal
- 1. 1 ANALGESIA MULTIMODAL : Sinergia en el manejo del dolor ALEJANDRO MELO FLORIÁN M.D. Especialista en Medicina Interna PUJ Miembro de Número ACIN Miembro Adscrito ACN
- 2. 2 Bases neurales de dolor
- 3. 3
- 4. 4 Definición de dolor “Experiencia sensorial y emocional desagradable asociada a lesión tisular real o potencial” “Posee cualidad urgente y primordial, responsable de aspecto afectivo y emocional” International Association for the Study of Pain Kandell E et al: Principles of Neural Sciences 2000
- 5. 5 Dolor agudo • Es la consecuencia inmediata de la activación de los sistemas nociceptivos por una noxa • Función de protección biológica (alarma en tejido lesionado). • De naturaleza nociceptiva, aparece por estimulación química, mecánica o térmica de nociceptores específicos. House A, Pansky B, Siegel A: Neurociencias. Enfoque sistemático. 1ª Edición en Español. Edit. McGraw-Hill, México D.F. pp. 138
- 6. 6 Nocicepción • “Proceso neural de codificar y procesar estimulos nocivos por vías neurales sanas, desencadena respuesta autonómica, sin que necesariamente produzca sensación de dolor” Loeser JD & Treede RD: The Kyoto Protocol of IASP Basic Pain Terminology. Pain 2008; 137; 473-477
- 7. 7 Dolor crónico • Sin función protectora. • Es enfermedad: síndrome doloroso • Incapacitante, con implicaciones sociales y económicas. • Requiere tratamiento multimodal Argoff CE et al. Multimodal analgesia for chronic pain: rationale and future directions. Pain Med. 2009;10(Suppl 2):S53-66.
- 8. 8 Neuroquímica en dolor • Estímulo intenso estimula fibras amielínicas Aδ y C de alto umbral, liberan – Sustancia P, Glutamato y Péptido relacionado con gen de calcitonina o CGRP. • Inducen despolarización de neuronas de segundo orden • Se transmite información hacia centros superiores Chaouch A, Besson JM. Peripheral and spinal mechanisms of nociception. Rev Neurol (Paris). 1986;142(3):173-200.
- 9. 9 Vías neurales Con modificaciones de. Jones A, Georgiou G. Probing Pain Biol Sci Rev 2006 Nov: 7-10
- 10. 10 Neuroquímica en dolor • La transmisión excitatoria en vía a corteza, es modulada por sistemas inhibitorios – Transmisores y receptores que disminuyen liberación de transmisores excitatorios y excitabilidad neuronal – opioides, α-adrenérgico, colinérgico, gabaérgico, canabinérgico • Se activan por el estímulo doloroso y actúan sinérgicamente con el sistema excitatorio Giordano J: The neurobiology of nociceptive and antinociceptive systems. Pain Physician 2005; 8: 277-290
- 12. 12 Sistema Canabinoide • Receptores CB1 - CB2 • Endocanabinoides: – Anandamida (AEA) – 2-Araquidonilglicerol (2-AG) – Noladina – Virodamina – N‑ araquidonil‑ dopamina (NADA) – Araquidonil serina (ARA‑ S) Burstein SH et al: Cannabinoids, Endocannabinoids, and Related Analogs in Inflammation. AAPS J. 2009 March; 11(1): 109–119. doi: 10.1208/s12248-009-9084-5
- 13. 13 Anandamida en ganglios A.G. Hohmann & M. Herkenham. Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience 1999; 90(3): 923–931
- 14. 14 Anandamida en espinas dendríticas V.M Pickela et al: Compartment-specific localization of cannabinoid 1 (CB1) and μ-opioid receptors in rat nucleus accumbens. Neuroscience 2004; 127(1): 101–112
- 15. 15 Receptores de anandamida en ME lumbar V.M AG Hohmann Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives Chemistry and Physics of Lipids 2002; 121(1-2) 173-190
- 16. 16 Receptores de anandamida en piel Ständer S et al. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin J Dermatological Sci 2005; 38(3): 177–188
- 17. 17 Sobre anandamida • La ubicuidad de receptores de anandamida en diferentes niveles del SNC hace racional las intervenciones farmacológicas como mecanismo de analgesia multimodal.
- 18. 18 Aumento de concentración de anandamida Moléculas IC50 µmol Oxaprozin 85 Flurbiprofeno 215 Fenoprofeno 530 Ketoprofeno 380 Naproxeno 710
- 20. 20 Impacto de condiciones OMA dolorosas • En LAM sobre 19.000 individuos, 1 de cada 4 reportó condiciones dolorosas OMA de origen diferente a traumático en los 7 días previos a encuesta. Suárez-Almazor ME. High burden of rheumatic disease in Mexico: a comprehensive community-based epidemiological study. J Rheumatol. 2011 Jan;38(1):8-9.
- 21. 21 Impacto de OA Ruiz Marco MC, Esteva Spinetti MH. Epidemiología de la osteoartrosis en el Hospital Central de San Cristóbal. Archivos de Reumatología. 2002, 9 (1):23 - ss
- 22. ¿Por qué se incrementa mortalidad 22 en OA? Incremento en la enfermedad isquémica cardíaca Sedentarismo y morbilidad asociada Uso frecuente de AINES y analgésicos. Morbilidad gastrointestinal Uso inadecuado de analgésicos Ryder JJ et al. Genetic associations in peripheral joint osteoarthritis and spinal degenerative disease: a systematic review. Ann Rheum Dis. 2008; 67: 584-91 Hochberg MC. Mortality in osteoarthritis. Clin Exp Rheumatol. 2008; 26: S120-4
- 23. 23 Exacerbaciones inflamatorias de OA y AINES • EULAR y OMS exigen que AINE no tenga efecto perjudicial sobre cartílago artrósico o normal. • Exacerbación inflamatoria de OA no incluída en CIE10 • AINES: Justificados para manejo de sinovitis – Sinovitis temprana en 47% de pacientes con OA CIE 10 D'Agostino MA, et al. EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part1: prevalence of inflammation in osteoarthritis. Ann Rheum Dis. 2005 Dec;64(12):1703-951-760
- 24. 24 Sinovitis en pacientes con OA dolorosa de rodilla D'Agostino MA, et al. EULAR report on the use of ultrasonography in painful knee osteoarthritis. Part1: prevalence of inflammation in osteoarthritis. Ann Rheum Dis. 2005 Dec;64(12):1703-951-760
- 25. 25 Dolor central en OA • La inflamación de membrana sinovial o de hueso subcondral facilita la llegada de impulsos dolorosos a la médula espinal (alodinia en SNC) • Mecanismo periférico desencadena plasticidad central para transmisión de dolor. • Anandamida brinda analgesia endógena MacDougall J. Arthritis and pain: Neurogenic origin of joint pain Arthritis Research & Therapy 2006, 8:220 (doi:10.1186/ar2069)
- 26. 26 Dolor central en OA • Alodinia en SNC en OA plantea : – falta de respuesta a los AINES tradicionales – Aumento de dosis de AINES, riesgo de complicaciones – Requerimiento de analgésicos adicionales. • Manejo de Alodinia: – Aumento de analgésicos centrales – Estimulación de ANANDAMIDA MacDougall J. Arthritis and pain: Neurogenic origin of joint pain Arthritis Research & Therapy 2006, 8:220 (doi:10.1186/ar2069)
- 27. 27 Terapéutica con analgésicos & AINES
- 28. 28 Aspectos Generales • Analgésicos como tramadol en dolor mostraron mínimos beneficios en OA. • Las guías clínicas recomiendan preferencia de codeína + acetaminofén. Altman RD: Practical Considerations for the Pharmacologic Management of Osteoarthritis. Am J Manag Care 2009 Sep;15(8 Suppl):S236-43.-
- 29. 29 Aspectos Generales • Revisión Cochrane mostró que aunque acetaminofén individual mostró eficacia al medir Respuesta al Dolor, HAQ, Evaluación Global de Médico, NO LA MOSTRÓ al evaluar con índice WOMAC o con índice de Lequesne Altman RD: Practical Considerations for the Pharmacologic Management of Osteoarthritis. Am J Manag Care. 2009 Sep;15(8 Suppl):S236-43. Towheed TE, Maxwell L, Judd M, Catton M, Hochberg MC, Wells GA. Acetaminophen for osteoarthritis. Cochrane Database Syst Rev. 2006;(1):CD004257
- 30. Dolor central: manejo con otros ppios activos Gabapentin for pain. New evidence from hidden data. Therapeutic Letter, 2009; issue 75, July- December
- 31. 31 Aspectos sobre uso de AINES en patología OM • El cambio de un AINE a otro es justificable cuando se tienen en cuenta efectividad terapéutica y efectos adversos y/o toxicidad • Es preferible el uso de AINE con acción multifactorial.
- 32. 32 Consideraciones prácticas • Guías de OARSI recomiendan uso de AINES con dosis más baja posible • El riesgo CVS es mayor con los inhibidores COX-2 altamente selectivos Altman RD: Practical Considerations for the Pharmacologic Management of Osteoarthritis. Am J Manag Care. 2009 Sep;15(8 Suppl):S236-43.-
- 33. 33 AINES y Analgesia Multimodal
- 34. 34 AINES en analgesia multimodal • Al ser usados como terapia multimodal en regímenes analgésicos, los AINES reducen los efectos colaterales de los opioides y contribuyen a mejores resultados funcionales. Reuben SS: Update on the role of nonsteroidal anti-inflammatory drugs and coxibs in the management of acute pain. Curr Opin Anaest 2007; 20(5): 440-450
- 35. 35 Controversias de AINES en analgesia multimodal • Uso de AINES convencionales plantea seguridad GI, CVS, renal entre otros. Shah S & Mehta V. Controversies and advances in non-steroidal anti-inflammatory drug (NSAID) analgesia in chronic pain management Postgrad Med J 2012;88:73e78. doi:10.1136
- 36. 36 COX-2 por inmunohistoquímica Solari V. Cyclooxygenase-2 Up-Regulation in Reflux Nephropathy J Urol 2003; 170(4 Part 2): 1624– 1627
- 37. 37 COX-2 en riñón Melk A et al. Expression of p16INK4a and other cell cycle regulator and senescence associated genes in aging human kidney. Kidney International 2004; 65, 510–520; doi:10.1111/j.1523- 1755.2004.00438.x
- 38. 38 Inhibición COX-2 a nivel renal • Inhibidores altamente selectivos de COX2 pueden producir – Retención hidrosalina – Hipertensión – Exacerbación de insuficiencia cardíaca congestiva. • Pgs de vía COX2 en riñón están involucradas en metabolismo hidrosalino y regulación de la presión arterial Warner TD, Mitchell JA. Cyclooxygenases: new forms, new inhibitors, and lessons from the clinic. FASEB J. 2004 May;18(7):790-804
- 39. 39 Tipos de inhibidores COX-2 Nimesulida Oxaprozin Selectividad COX-1 Selectividad COX-2 Warner TD, et al. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA. 1999; 96:7563-7568
- 40. Coexistencia de factores de 40 riesgo GI para uso de AINES Lanas A, et al. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med 2011 Apr 14;9:38
- 41. Coexistencia de riesgo GI y CV 41 para uso de AINES Lanas A, et al. Prescription patterns and appropriateness of NSAID therapy according to gastrointestinal risk and cardiovascular history in patients with diagnoses of osteoarthritis. BMC Med. 2011 Apr 14;9:38
- 42. 42 AINE ideal • Rápido inicio de acción • Mecanismos complementarios • Tolerabilidad gástrica • Seguridad cardiovascular y renal • Cómoda dosificación • Eficacia anti-inflamatoria • Eficacia analgésica
- 43. 43 Perspectivas de Oxaprozin como AINE ideal
- 44. 44 Descripción de Oxaprozin Derivado del ácido propiónico Anti- inflamatorio analgésico • Doble acción analgésica • Mejor perfil de seguridad (sin enantiómeros) • Novedosa estructura química • Superiores propiedades farmacocinéticas Oxaprozin Lewis AJ, et al. The pharmacological profile of Oxaprozin Curr Ther Res 1983;34: 777-94 Caldwell J.R. Summary profile of Oxaprozin: comparison with other NSAIDs Seminars Arth Rheum 1986; 15(Suppl. 2): 101-107
- 45. 45 Mecanismos de acción • Inhibición preferencial de la COX2 • Mecanismos anti-inflamatorios adicionales – Inhibe moléculas que multiplican respuesta inflamatoria – Control células inflamatorias • Analgesia por doble vía: Inhibición de Pgs y aumento de anandamida Dallegri,F; Ottonello,L: Pharmacological implications in the switch from acute to chronic inflammation Inflammopharmacology 2002; 10: 159-17
- 46. 46 Mecanismo de acción • Oxaprozin evita reclutamiento de nuevos monocitos: evita que inflamación aguda pase a crónica • Promueve apoptosis de monocitos activados: detiene curso de inflamación crónica Dallegri F, Bertolotto M, Ottonello L. A review of the emerging profile of the anti-inflammatory drug oxaprozin. Expert Opin Pharmacother 2005; 6(5): 777-85
- 47. 47 Mecanismo de acción Dallegri F, Bertolotto M, Ottonello L. A review of the emerging profile of the anti-inflammatory drug oxaprozin. Expert Opin Pharmacother 2005; 6(5): 777-85
- 49. 49 Farmacocinética McMillen JA: A review of the pharmacokinetics of oxaprozin in compromised patients. Drug Ther 1993 Suppl March 53-60
- 50. 50 Mejoría de dolor por Oxaprozin Kean WF et al. A critical assessment of Oxaprozin clinical profile in rheumatic diseases. Inflammopharmacology, 2002; 10 (3): 241-284.
- 51. 51 Seguridad comparativa de Oxaprozin Kean WF et al. A critical assessment of Oxaprozin clinical profile in rheumatic diseases. Inflammopharmacology, 2002; 10 (3): 241-284.
- 52. 52 Perfil de Seguridad digestivo • PSUR Rare: > a 1: 1000. PSUR
- 53. 53 Perfil de seguridad CVS Brinker A, et al. Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin. Drugs Aging. 2004;21(7):479-84
- 54. 54 Perfil de seguridad renal • PSUR PSUR
- 55. 55 Perfil de seguridad • PSUR PSUR
- 56. Comparación AINES de uso frecuente 56
- 57. 57 Mensaje para llevar a casa • Gran incidencia de problemas OMA en población general • Inhibición altamente selectiva de COX2 retiene líquidos y Na: problemas CVS • Es frecuente coexistencia de F. de R. GI y CV • Sinovial juega papel importante en OA • Dolor central tiene implicación terapéutica en OA
- 58. 58 ¿Por qué Oxaprozin? • AINE con mecanismos adicionales de acción – Sinergia multimodal en el manejo del dolor • La mejor relación eficacia / seguridad por meta-análisis • Más de 4.5 millones de prescripciones anuales en EE.UU. • Soporte de uso a largo plazo • Perfil de seguridad GI y CVS sin cambios desde 1991
- 59. Gracias, gràcies, thanks, merci, obrigado, спасибо, danke, grazie, arigatoo alejandromeloflorian@gmail.com
Notes de l'éditeur
- Chronic pain is a multifaceted disease requiring multimodal treatment. Clinicians routinely employ various combinations of pharmacologic, interventional, cognitive-behavioral, rehabilitative, and other nonmedical therapies despite the paucity of robust evidence in support of such an approach. Therapies are selected consistent with the biopsychosocial model of chronic pain, reflecting the subjective nature of the pain complaint, and the myriad stressors that shape it. Elucidating mechanisms that govern normal sensation in the periphery has provided insights into the biochemical, molecular, and neuroanatomic correlates of chronic pain, an understanding of which is leading increasingly to mechanism-specific multidrug therapies. Peripheral and central neuroplastic reorganization underlying the disease of chronic pain is influenced by patient-specific emotions, cognition, and memories, further impairing function and idiosyncratically defining the illness of chronic pain. Clinical perceptions of these and related subjective elements associated with the suffering of chronic pain drive psychosocial treatments, including, among other options, relaxation therapies, coping skills development, and cognitive-behavioral therapy. Treatment selection is thus guided by comprehensive assessment of the phenomenology and inferred pathophysiology of the pain syndrome; patient goals, preferences, and expectations; behavioral, cognitive, and physical function; and level of risk. Experiential, practice-based evidence may be necessary for improving patient care, but it is insufficient; certainly, well-designed studies are needed to support therapeutic decision making. This review will discuss the biochemical basis of pain, factors that govern its severity and chronicity, and foundational elements for current and emerging multimodal treatment strategies.
- O
- Volume 90, Issue 3 , May A.G. Hohmann & M. Herkenham. Localization of central cannabinoid CB1receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study. Neuroscience 1999; 90(3): 923–931
- Electron micrographs showing CB1 receptor immunogold labeling (small arrows) in axon terminals forming either an asymmetric synapse with a dendritic spine in the Acb shell (A) or a symmetric synapse with a larger dendrite in the Acb core (B). These target spines and dendrites exhibit diffuse immunoperoxidase labeling for μ- opioid receptor throughout their cytoplasm (Mu-s and Mu-d, respectively). In B, one terminal (Dt) contains both immunogold CB1 receptor and immunoperoxidase labeling for μ- opioid receptor. The peroxidase immunoreactivity is particular dense along a membranous structure presumed to be smooth endoplasmic reticulum (ser). This terminal forms a punctate junction with an unlabeled dendritic spine. Scale bars=0.5 μ m
- AG Hohmann Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives Chemistry and Physics of Lipids 2002; 121(1-2)173-190 Volume 121, Issues 1–2 , 31 December 2002, Pages 173–190 Review , Chemistry and Physics of Lipids Volume 121, Issues 1–2 , 31 December 2002, Pages 173–190 Review Spinal and peripheral mechanisms of cannabinoid antinociception: behavioral, neurophysiological and neuroanatomical perspectives Andrea G. Hohmann ,
- Journal of Dermatological Science Fig. 2. Immunoreactivity for CB1 on nerve fiber bundles in normal human skin from the face. Positive immunoreactivity for CB1 in a large (A, arrow) and a small subepidermal (D, arrow) nerve fiber. The neuronal markers neurofilament (B, arrow) and protein gene product 9.5 (PGP 9.5, E, arrow) show intense immunoreactivity in axons. In the overlay, the presence of CB1 on several axons in a large myelinated nerve fiber bundle (C, arrow), a mast cell next to the nerve fiber (arrowhead) and a subepidermal small nerve fiber (F, arrow) can be seen. Interestingly, basal keratinocytes stain intensely for PGP 9.5 (E) while CB1 stains suprabasal keratinocytes (D). Bar: A–C, 7 μ m; D–F, 34 μ m.
- The prevalence of US features suggestive of an inflammatory process, either synovitis or effusion, was quite high (47%). A large group of patients also had US detected effusion and no detectable synovitis (30%). These findings may reflect the strict definitions of synovitis and effusion employed in this study; and, possibly, microscopic synovitis may exist in the absence of US detected synovial hypertrophy. We found those subjects with knee OA with a more severe radiological grade (K&L grade >3) and moderate or important knee joint effusion on clinical examination had an increased probability of synovitis being detected at US examination (odds ratio (OR)=2.20 and 1.97, respectively).
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1755310/?tool=pubmed
- MacDougall J. Arthritis and pain: Neurogenic origin of joint pain Arthritis Research & Therapy 2006, 8: 220 (doi:10.1186/ar2069) http://arthritis-research.com/content/8/6/220
- MacDougall J. Arthritis and pain: Neurogenic origin of joint pain Arthritis Research & Therapy 2006, 8: 220 (doi:10.1186/ar2069) http://arthritis-research.com/content/8/6/220
- http://www.foroaps.org/files/kludjyfs.pdf
- Gastrointestinal (GI) bleeding and ulceration, thrombotic events such as myocardial infarction and stroke, renal impairment, fluid retention and exacerbation of asthma are some of the side effects of NSAIDs NSAID combination drugs with gastric protection have provided alternatives to traditional NSAIDs, but the long term sequelae are unknown.
- Gastrointestinal (GI) bleeding and ulceration, thrombotic events such as myocardial infarction and stroke, renal impairment, fluid retention and exacerbation of asthma are some of the side effects of NSAIDs NSAID combination drugs with gastric protection have provided alternatives to traditional NSAIDs, but the long term sequelae are unknown.
- COX-2 immunohistochemistry. A , lack of COX-2 immunoreactivity in proximal tubules, glomerulus and macula densa (arrow) in normal kidney. B , RN kidney with strong COX-2 immunoreactivity in tubules and moderate expression in macula densa (arrow). Reduced from ×400.
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101123/
- http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3101123/
- Descripción Oxaprozin Oxaprozin, el principio activo de Duraprox ® , es un derivado del ácido propiónico, que pertenece al grupo de los agentes antiinflamatorios no-esteroideos o AINES, que a diferencia de otros de la clase, posee características particulares que lo diferencian de forma notable de los demás miembros de la familia de derivados propiónicos, como ibuprofeno, diclofenaco. Duraprox inhibe de manera no selectiva las ciclooxigenasas, es decir que inhibe tanto la COX-1 como la COX-2, razón por la cual es un potente inhibidor de la síntesis de prostaglandinas, gracias a lo cual ejerce un efecto anti-inflamatorio con acción analgésica. Muchos de los AINES, algunos de los cuales son derivados del ácido propiónico, poseen centros de quiralidad dentro de su estructura molecular; a diferencia de las formas R o S, oxaprozin no posee enantiómeros, lo que significa que no hay otras moléculas con actividad farmacológica adicional. La quiralidad tiene efectos notables sobre la toxicidad y las interacciones de la molécula. La molécula está compuesta una parte propiónica alifática hidrofìlica y una lipofílica con anillos cíclicos y heterocíclicos, como puede apreciarse en la gráfica. Esta estructura es novedosa, y le brinda a Duraprox ® características farmacocinéticas especiales, como es el caso de la elevada concentración que alcanza en los tejidos sinoviales por su lipofilia. Oxaprozin, es un ácido débil con un Pka de 4.3-5.2 en agua, gracias a lo cual tiene poca difusión a mucosa gástrica lo cual es responsable de su seguridad digestiva.
- Hemodializados DURAPROX Clin Pharmacol Ther. 1988 Sep;44(3):303-9. Effect of chronic renal failure on oxaprozin multiple-dose pharmacokinetics. Audet PR , Knowles JA , Troy SM , Walker BR , Morrison G . Source Renal Electrolyte Section, Hospital of the University of Pennsylvania, Philadelphia. Abstract The effects of renal disease on the steady-state kinetics of oxaprozin were assessed in eight patients on hemodialysis with normal serum albumin levels and eight normal subjects who received six doses. A larger clearance and volume of distribution at steady state for total and unbound oxaprozin occurred in the patients on hemodialysis. The elimination half-lives were not different. The mean total AUC, peak concentration, average steady-state plasma concentration, and trough concentration for total and unboundoxaprozin were decreased in the patients on hemodialysis. These differences are consistent with impaired absorption of oxaprozinin patients on hemodialysis. The higher dose-averaged unbound fraction of oxaprozin in plasma in patients on hemodialysis may be caused by endogenous binding inhibitors. Because clearance was not reduced in patients on hemodialysis, the dose of oxaprozinmay not need to be reduced when albumin levels are normal. In some patients oxaprozin may cause reversible elevations of blood urea and creatinine levels. Patients at risk of impairment of renal function are those with already compromised renal blood flow (i.e. those with sodium restriction or volume depletion, on concomitant diuretic therapy or with pre-existing renal impairment, congestive heart failure, liver cirrhosis or elderly patients particularly with low lean body mass). http://www.fda.gov/ohrms/dockets/ac/02/briefing/3882b2_06_international%20ibuprofen%20foundation.htm The incidence of adverse events is summarised in Table 1. Significant adverse events were reported by 18.7% of patients taking aspirin, 13.7% of those taking ibuprofen and by 14.6% of those taking acetaminophen (p<0.001 for aspirin vs. ibuprofen). Significant gastrointestinal events were less frequent with ibuprofen (4.0%) than with aspirin (7.1%, p<0.001) or acetaminophen (5.3%) (p=0.025), in particular dyspepsia (1.4% vs. 3.1% with aspirin, p<0.001; and 2.2% with acetaminophen, p<0.019), abdominal pain (2.8% vs. 6.8% with aspirin, p<0.001; and 3.9% with acetaminophen, p<0.24); nausea was more frequent with aspirin (2.5%) than ibuprofen (p=0.01) or acetaminophen (1.5% each). There were no significant differences between the treatments in events associated with other organ systems. Subgroup analysis showed that the risk of adverse effects was not significantly different by age, sex and indication. Riesgo >Hospitalizac con naproxeno: 7.9 de sangrado digestivo J Rheumatol. 2005 Nov;32(11):2212-7. Risk of hospitalization with peptic ulcer disease or gastrointestinal hemorrhage associated with nabumetone, Arthrotec, diclofenac, and naproxen in a population based cohort study. Ashworth NL , Peloso PM , Muhajarine N , Stang M . RESULTS: Compared to Arthrotec the adjusted odds of hospitalization for PUD for participants taking nabumetone was 2.6 (95% CI 1.0-6.6), diclo+coRx 6.8 (95% CI 3.5-13.4), and naproxen 7.9 (95% CI 3.9-15.9). Compared to nabumetone the adjusted odds of hospitalization for PUD for participants taking diclo+coRx was 2.7 (95% CI 1.2-6.0) and naproxen 3.1 (95% CI 1.3-7.1). No significant differences were noted in terms of admissions for GI hemorrhage 4.9 de sangrado con oxaprozin Clin Ther. 1998 Nov-Dec;20(6):1218-35; discussion 1192-3. Economic and gastrointestinal safety comparisons of etodolac, nabumetone, and oxaprozin from insurance claims data from patients with arthritis. Simon LS , Zhao SZ , Arguelles LM , Lefkowith JB, Dedhiya SD, Fort JG, Johnson KE. In outpatient settings, 3.9%, 4.2%, and 4.9% of the etodolac-, nabumetone-, and oxaprozin-ONLY patients, respectively (P > 0.05), and 6.0%, 5.3%, and 4.7% of the etodolac-, nabumetone-, and oxaprozin-PLUS patients, respectively, had at least one upper GI ulcer/bleeding claim (P > 0.05). The proportions of patients with NSAID-induced and possibly NSAID-induced GI admissions were 0.1% and 0.4% for the etodolac-ONLY, 0.3% and 1.0% for the nabumetone-ONLY, and 0.1% and 0.5% for the oxaprozin-ONLY groups, respectively (P > 0.05), and a similar pattern was observed among the PLUS groups. Mayor elevacion de aminotransferasas sale de Diclofenac was associated with higher rates of aminotransferase elevations compared with users of other NSAIDs, but not with a higher incidence of serious liver disease naproxen, 29.2% (24.8% - 33.6%); nimesulide, 20.2% (16.0% - 24.3%); ibuprofen, 16.7% (14.7% - 18.8%); diclofenac, 19.3% (11.9% - 26.7%); oxaprozin, 12.7% (8.9% - 16.7%); salen de Shi W, Wang YM, Cheng NN, Chen BY, Li D. [Meta-analysis on the effect and adverse reaction on patients with osteoarthritis and rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs]. Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Nov;24(11):1044-8 Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Nov;24(11):1044-8. [Meta-analysis on the effect and adverse reaction on patients with osteoarthritis and rheumatoid arthritis treated with non-steroidal anti-inflammatory drugs]. [Article in Chinese] Shi W, Wang YM, Cheng NN, Chen BY, Li D. Source Department of Pharmacology, College of Pharmacy, Fudan University, Shanghai 200032, China. Abstract OBJECTIVE: To observe the rate of efficacy and adverse drug reaction of non-steroidal anti-inflammatory drugs (NSAIDs) in the population with osteoarthritis and rheumatoid arthritis, based on available clinical data. METHODS: Using Meta analysis to evaluate the data of effect and safety profile of NSAIDs from 19 articles on randomized clinical trials published from 1990 to 2001 in Chinese journals. The total number of patients enrolled for evaluation on rates of effectiveness and adverse drug reaction were 1 732 and 2 925, respectively. RESULTS: Data on the effect and safety were comparatively heterogeneous among different kinds of NSAIDs. The effective rates (95% CI) were as follows: nabunetone, 66.7% (61.9% - 71.4%); meloxicam, 68.4% (59.2% - 77.6%); naproxen, 64.5% (59.8% - 69.1%); nimesulide, 79.8% (75.7% - 84.0%); ibuprofen, 77.2% (70.7% - 83.8%); diclofenac, 77.1% (69.2% - 85.0%); oxaprozin, 65.8% (59.5% - 72.0%). Rates of adverse drug reaction (95% CI) were as follows: nabunetone, 16.3% (12.5% - 20.0%); meloxicam, 10.2% (4.2% - 16.2%); naproxen, 29.2% (24.8% - 33.6%); nimesulide, 20.2% (16.0% - 24.3%); ibuprofen, 16.7% (14.7% - 18.8%); diclofenac, 19.3% (11.9% - 26.7%); oxaprozin, 12.7% (8.9% - 16.7%) respectively . CONCLUSION: The rates of effect and adverse reaction on patients having osteoarthritis and rheumatoid arthritis with NSAIDs treatment would largely depend on the drugs being used. Within 2 - 8 weeks of treatment, the effective rate and rate of adverse drug reaction with commonly used NSAIDs as nabumeton, meloxicam, etc., were 59.2% - 85.0% and 4.2% - 33.6%, respectively. PMID: 14687510 [PubMed - indexed for MEDLINE] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3019238/pdf/bmj.c7086.pdf