ObjecIves. Acetaminophen and NSAID Use in Athletes. Types of Injuries. Acute Injuries. Injury InflammaIon 12/16/12

Transcription

1 ObjecIves Acetaminophen and NSAID Use in Athletes Team Physician Course Feb 2013 Heather Gillespie, MD, MPH Assistant Professor, UCLA Team Physician, UCLA AthleIcs Review normal healing process and types of injuries treated with these medicaions Review risks and benefits of acetaminophen use in athletes Review risks and benefits of NSAID use in athletes Acute Sprain Strain Chronic Overuse, overload Fractures Acute/Stress Types of Injuries Acute Injuries What happens when Issues are acutely injured? Injury InflammaIon Injury InflammaIon 1

2 How Does the Body Heal? Achieve Homeostasis? Healing Process Inflammatory phase (Injury to hrs) Remove debris, damaged Issue. Recruit cytokines and other growth factors. May also be integral to muscle repair and adapta/on. ProliferaIve phase (48 hrs 6 weeks) ProteolyIc degradaion of damaged Issue facilitated by protein- rich exudate resuling from vascular permeability. Proteolysis a_racts neutrophils, lymphocytes, macrophages. Fibroblasts form new extracellular matrix. MaturaIon phase (6 weeks months) New extracellular matrix. FuncIonal Issue is laid down. Each phase is dependent upon the preceding phase! Good or Evil??? InflammaIon InflammaIon is a necessary component in the healing process! "inflammaion can occur without healing, but healing cannot occur without inflammaion. Leadbe_er Chronic/Overuse Tendini/s: "iis" = inflammatory process these injuries may not be inflammatory in nature! Tendinosis: tendon degeneraion Tendinopathy: nonspecific tendon pathology Tendinopathy TheoreIcal Model of Tendinosis cycle: Adequate Repair (AdaptaIon) Increased Demand on Tendon Acetaminophen and NSAIDs What do they have in Common?? Analgesic AnIpyreIc PredisposiIon to Further Injury Tendinosis Cycle Inadequate Repair (Inadequate collagen and matrix producion) Further reducion in collagen and matrix producion Tenocyte Death 2

3 Mechanism of AcIon NSAID COX inhibitor (block prostaglandin formaion) Acetaminophen central acing Debate on mechanism of acion May have weak COX inhibiion Acetaminophen N- acetyl- p- aminophenol (APAP) First marketed as children s elixir in US in 1955 Approx 184 OTC and Rx APAP avail Preg risk factor B Safe in breaskeeding Acetaminophen Risks Liver Toxicity Thousands of ER visits/yr Overdose is biggest issue Acute liver failure (hepaic necrosis) Btw , 1600 cases of acute liver failure in US/yr. 86% a_ributed to intenional and unintenional APAP overdose 2011 Acetaminophen Risks FDA Boxed Warning potenial for severe liver injury Warning potenial for allergic reacions (e.g., swelling of the face, mouth, and throat, difficulty breathing, itching, or rash) Increased liver toxicity risk with consumpion of 3 or more alcoholic drinks per day with APAP use Acetaminophen Risks January 2011: FDA limited strength of acetaminophen in prescripion drug products to 325 mg per tablet/ capsule >4g/day = potenially toxic Advised max daily dose = 3g/day 3

4 NSAIDs Non- Steroidal AnI- Inflammatory Drugs (NSAIDs) Analgesic AnI- inflammatory AnIpyreIc NSAIDs Mechanism of acion: Block formaion of prostaglandins through inhibiion of cyclooxygenase (COX) enzymes 17,000,000 Americans use various NSAIDs on a daily basis One of most commonly used class of drugs in the world COX- 1 enzyme Homeosta/c (cons/tu/ve enzyme; responsible for regula/on of normal cell ac/vity) Form prostaglandins for: ProtecIon of gastric mucosa Platelet acivaion Macrophage differeniaion Maintenance of some renal funcions COX 2 enzyme Inducible (Pathologic) Form prostaglandins for: InflammaIon Pain Fever AND Bone formaion Tissue repair ater injury (collagen synthesis) Physiologic reproducion and renal funcion Healing of H. Pylori gastric ulcers NSAIDs GI RISK Symptoms: dyspepsia, nausea, heartburn, consipaion G- I bleeding: (dose- related) Direct effect/irritaion Systemic (post- absorpive) prostaglandin inhibiion of endogenous mucosal protecion (cytoprotecive effect) NSAIDs GI RISK GI bleeding secondary to NSAID use is the 15th leading cause of death in the United States > 100,000 hospitalizaions annually 5-10% mortality rate in those hospitalized for NSAID- induced GI bleed Increased risk Increased age (> 65), simultaneous use with another NSAID, alcohol use, coricosteroid use, anicoagulant use 4

5 NSAIDs GI RISK Ater 7 day use: 6.7% incidence gastric ulceraion 1.4% duodenal ulceraion COX- 2s safer? Compared to placebo, COX- 2s sill have 5x risk of bleeding NSAID GU RISK Risk of acute renal failure 5% who use NSAIDs experience renal complicaions Prostaglandin- induced decreased renal blood flow Complicates prolonged exercise/heat- induced hypovolemia Inc risk of hyponatremia Electrolyte imbalance (prostaglandin inhibiion) HepaIc Risk Unusual (< 5/100,000 users per year) CombinaIon with other hepatotoxic drugs increases risk i.e. acetaminophen Cardiac Risk May accelerate CHF in at- risk individuals SelecIve inhibiion of anithromboic prostaglandins (COX 2) might increase cardiovascular events?? Mechanism: increased vascular resistance interference with acions of diureics, ACE inhibitors Cardiac Risk Cardiac Risk Celecoxib 400 mg twice daily linked to 3.4- fold increase in CV death, MI, CVA 200 mg twice daily 2.4- fold increase CV risk greatest ater 18 months of use New data: Even shorter dura/on has risk! 5

6 Bleeding Risk Interferes with platelet funcion/aggregaion Specific Concern For the Sports Medicine Physician: Delayed Healing?? Animal Studies: Sprains Animal Studies: Sprains The effect of a nonsteroidal an5inflammatory drug on the healing of ligaments. Dahners, et al. AJSM, Results of animal studies show increased mechanical strength during healing, presumably due to increased collagen cross- linking. Once healed, however, there were no differences between placebo and NSAID- treated ligaments. A cyclooxygenase- 2 inhibitor impairs ligament healing in the rat. Elder CL, et al. AJSM Evaluated effects of COX- 2 inhibitor (Celecoxib) Inhibited early healing of incised rat MCL s. Celecoxib- treated/injured ligaments were found to have a 32% lower load to failure than untreated/injured ligaments. No effect on uninvolved, healthy ligaments. The effect of analgesic agents on the healing rat medial collateral ligament. Hanson CA, et al. AJSM Transected rat MCLs Tx groups: piroxicam, naproxen, rofecoxib, butorphanol, 2 doses of acetaminophen, and control Mechanical tesing on day 14 post op Piroxicam group demonstrated significantly greater load to failure (27%) compared with the control No sig difference with opiate analgesics, acetaminophen, and cyclooxygenase- 2 inhibitors Contradicted 1988 study. NegaIve effect on ligaments is more profound with COX- 2 Inhibitors NSAIDs and Sprains A randomized controlled trial of piroxicam in the management of acute ankle sprain in Australian Regular Army recruits. Slatyer MA, et al. AJSM army recruits with ankle sprains Randomized to piroxicam or placebo Piroxicam group: less pain & able to resume training faster However some evidence of local abnormaliies: instability and reduced ROM Unknown long term effect on /ssue healing and structure NSAIDs and Sprains Summary: ContradicIng results: Piroxicam: simulate collagen synthesis and early strength? Some evidence of short term decreased ligament healing Detrimental effect on ligaments is more profound with COX- 2 Inhibitors VariaIons in cyclooxygenase enzyme selecivity by different drugs? VariaIon in analgesic properies? Unknown long term effect on Issue healing and structure Animal Studies = Clinical relevance? Inflamma/on is a necessary component in the healing process! 6

7 Animal Studies: Strains The effects of common an5- inflammatory drugs on the healing rat patellar tendon. Ferry ST, et al. AJSM Transected and sutured rat patellar tendons Mechanical tesing and biochemical analysis at 14 d post op NSAIDs (except ibuprofen) had decreased failure loads and increased failures of suture. Acetaminophen had no effect on healing strength Biomechanical properies paralleled closely with total collagen content at the injury site Suggests agents may alter healing strength by decreasing collagen content Strains NSAIDs may Delay and possibly decrease inflammaion Inc contracile force in early post- injury state But prostaglandins have a simulant effect on skeletal muscle protein synthesis Delayed muscle regeneraion? Dec collagen synthesis? Delayed effect on Issue level healing? Fracture Healing Prostaglandins important in the regulaion of osteoblast and osteoclast funcions Important for bone formaion, healing, and remodeling InhibiIon of prostaglandin producion retards bone formaion NSAIDs used to prevent ectopic bone formaion (heterotopic ossificaion) Documented in controlled clinical trials Fracture Healing Bone fracture healing Oral applicaion of diclofenac significantly delayed fracture healing in rats* Animal studies show inhibiion or deficiency of COX- 2 impairs the bone healing process Mice with COX- 2 knockout gene Reduced endochondral ossificaion and greater delayed union Limited clinical data supports assumpion that inhibiion of COX- 2 by non- selecive or COX- 2- selecive NSAIDs delays fracture healing *Beck A. et al. Arch Orthop Trauma Surg (2003) 123: NSAIDs and Fracture Healing Benefits Pain relief InhibiIon of ectopic bone formaion Risk Non- union Delayed union NSAIDs in MSK Injuries Animal studies show delayed fracture healing and delayed Issue regeneraion Cox- 2 inhibitors have an adverse effect on bone healing and may have an adverse effect on ligament healing Further invesigaion needed to confirm tradiional NSAIDs preferable for the healing of collagenous Issues? Need for studies on the effects of NSAIDs on clinical level Issue repair 7

8 ProphylacIc Use? Impair normal biofeedback Injury risk Impair normal healing response Collagen synthesis Acute GI Risk GI mucosal damage Acute Renal risk Hyponatremia Increased bleeding risk Summary Acute Analgesia is Important in Injury Treatment Earlier mobilizaion and return to funcion Consider Risks and Benefits in Acute Injuries Screen for comorbiiies Further research needed Avoid NSAID Use in Fracture Care Counsel on Risks of ProphylacIc NSAID Use Avoid Prolonged NSAID Exposure GI, Cardiac Risk Counsel on proper dosing of APAP Increase risk of overdose with EtOH References References ALMEKINDERS LC, GILBERT J. Healing of experimental muscle strains and the effects of nonsteroidal aniinflammatory medicaion. AJSM 1986; 14(4) Beck A. et al. Influence of diclofenac (group of nonsteroidal ani- inflammatory drugs) on fracture healing. Arch Orthop Trauma Surg 2003; 123: Dahners LE, et al. The effect of a nonsteroidal aniinflammatory drug on the healing of ligaments. Am J Sports Med Nov- Dec;16(6): Dahners LE, Mullis BH. Effects of nonsteroidal ani- inflammatory drugs on bone formaion and sot- Issue healing. J Am Acad Orthop Surg May- Jun;12(3): Eichner, ER. Intramuscular Ketorolac InjecIons: The Pregame Toradol Parade. Current Sports Medicine Reports: July/August 2012;11(4): Elder CL, et al. A cyclooxygenase- 2 inhibitor impairs ligament healing in the rat. Am J Sports Med Nov- Dec;29(6): Ferry ST, et al. The effects of common ani- inflammatory drugs on the healing rat patellar tendon. Am J Sports Med Aug;35(8): Epub 2007 Apr 23. Fransen M, Neal B. Non- steroidal ani- inflammatory drugs for prevening heterotopic bone formaion ater hip arthroplasty. Cochrane Database Syst. Rev. 2004; 3:CD Giannoudis PV, MacDonald DA, Ma_hews SJ, et al. Nonunion of the femoral diaphysis. The influence of reaming and non- steroidal aniinflammatory drugs. J. Bone Joint Surg. Br. 2000; 82: Goyal RK, et al. EffecIveness of FDA's new over- the- counter acetaminophen warning label in improving consumer risk percepion of liver damage. J Clin Pharm Ther. 2012; Epub Sep 7. Guggenheimer J, Moore PA. The therapeuic applicaions of and risks associated with acetaminophen use: a review and update. J Am Dent Assoc 2011;142(1): Hanson CA, et al. The effect of analgesic agents on the healing rat medial collateral ligament. Am J Sports Med May;33(5): Epub 2005 Feb 16. Hinz B, Brune K. Paracetamol and cyclooxygenase inhibiion: is there a cause for concern?ann Rheum Dis 2012;71: Leadbe_er WB. An introducion to sports- induced sot- Issue inflammaion, in Leadbe_er WB, Buckwalter JA, Gordon SL (eds): Sports- induced InflammaIon: Clinical and Basic Science Concepts. Park Ridge, IL, American Academy of Orthopaedic Surgeons, 1990, p 13 Murnaghan M, Li G, Marsh DR. Nonsteroidal ani- inflammatory drug induced fracture nonunion: an inhibiion of angiogenesis? J. Bone Joint Surg. Am. 2006; 88: O'Connor JP, Lysz T. Celecoxib, NSAIDs and the skeleton. Drugs Today (Barc) Sep;44(9): Pountos I, et al. Do nonsteroidal ani- inflammatory drugs affect bone healing? A criical analysis. ScienIficWorldJournal. 2012;2012: Epub 2012 Jan 4. Roth SH. Anderson S. The NSAID dilemma: managing osteoarthriis in high- risk paients. Phys Sportsmed 2011 Sep;39(3): Simon AM, Manigrasso MB, O Connor JP. Cyclo- oxygenase 2 funcion is essenial for bone fracture healing. J. Bone Miner. Res. 2002; 17: Simon AM, O Connor JP. Dose and Ime- dependent effects of cyclooxygenase- 2 inhibiion on fracture- healing. J. Bone Joint Surg. Am. 2007; 89:500Y11. Slatyer MA, Hensley MJ, Lopert R.A randomized controlled trial of piroxicam in the management of acute ankle sprain in Australian Regular Army recruits. The Kapooka Ankle Sprain Study. Am J Sports Med Jul- Aug;25(4): Stovitz SD, Johnson RJ. NSAIDs and Musculoskeletal Treatment. What Is the Clinical Evidence? THE PHYSICIAN AND SPORTSMEDICINE 2003; 31(1). VAN WIJCK, K. et al. AggravaIon of Exercise- Induced IntesInal Injury by Ibuprofen in Athletes. MSSE 2012; 44(12): Vuolteenaho K, et al. Non- steroidal ani- inflammatory drugs, cyclooxygenase- 2 and the bone healing process. Basic Clin Pharmacol Toxicol Jan;102(1):10-4. Epub 2007 Oct 31. Warden SJ. Cyclo- oxygenase- 2 inhibitors : beneficial or detrimental for athletes with acute musculoskeletal injuries? Sports Med. 2005;35(4):