Key Words: aspirin, COX-2 inhibitors, ibuprofen, NSAID, pharmacokinetics. 3 identifies clinical

Transcription

1 Pharmacology in Rehabilitation: Nonsteroidal Anti-inflammatory Agents Ross E. Biederman, DPM 1 Journal of Orthopaedic & Sports Physical Therapy Nonsteroidal anti-inflammatory agents (NSAIDs) are the most commonly encountered over-thecounter (OTC) and prescription medications in physical therapy practice. Worldwide, over prescriptions for nonsteroidal agents are written yearly. NSAIDs produce a wide range of beneficial effects to the physical therapy patient, enhancing the outcome of treatment. Helpful effects of NSAIDs include analgesia, antipyretic, anti-inflammatory, and antithrombotic properties. However, NSAIDs are also associated with frequent and significant side effects that are deleterious to treatment outcome, including delay in soft tissue and bone healing, renal and liver toxicity, hemorrhagic events, gastric irritation and ulceration, and central nervous system effects. Understanding of the pharmacological properties of these drugs, exemplified by aspirin, and the individual pharmacokinetics of specific preparations will help the therapist to screen patients for potential side effects, develop more effective plans of care, and, where allowed, effectively and safely prescribe NSAIDs. J Orthop Sports Phys Ther 2005;35: Key Words: aspirin, COX-2 inhibitors, ibuprofen, NSAID, pharmacokinetics The Guide to Physical Therapist Practice 3 identifies clinical pharmacology as an essential component of appropriate patient monitoring, modality delivery, and communication among medical professionals. The prescription-drug writing privileges exercised by select military therapists and the evolution of the physical therapy profession promote consideration of an expanded pharmacological role in physical therapy practice. Whether the individual practitioner acts to monitor or prescribe drug agents, the importance of a pharmacologically integrated approach to comprehensive patient management cannot be underestimated. By far the most frequently encountered and/or prescribed drug agents in physical therapy practice are the nonsteroidal antiinflammatory agents (NSAIDs). A sense of magnitude is gained by recognizing that NSAIDs are, in both their prescription and over-thecounter (OTC) forms, the most commonly utilized drug agents in the United States, and that worldwide over prescriptions are written yearly. 43 Of patients seeing physical therapists, 25% to 40% are taking prescription anti-inflammatory agents with about 40% of those using multiple NSAIDs concomitantly. 6,7 Using data from a multicenter physical therapy study, Boissonnault and Meek 8 report that 78.6% of patients seen for treatment had used aspirin or other OTC antiinflammatory agents within the prior week. 1 Diplomat, American Board of Podiatric Surgery, San Francisco, CA; Professor, Physical Therapy Department, Azusa Pacific University, Azusa, CA. I affirm that I have no personal associations, financial affiliations or involvement with any commercial organization that has a direct financial interest in any matter included in this manuscript. Address correspondence to Dr Ross Biederman, Physical Therapy Department, Azusa Pacific University, 901 E Alosta Avenue, Azusa, CA rbiederman@apu.edu NSAIDs are defined as a diverse group of drugs with the shared ability to (1) relieve pain, (2) decrease inflammation, (3) decrease elevated body temperature, and (4) decrease blood clotting (nonselective NSAIDs only) by inhibition of platelet aggregation. 15 Traditional nonselective NSAIDs are used to prevent recurrent stroke 26 and evidence is growing for the ability of select NSAIDs to delay progression of Alzheimer s Disease. 1 NSAIDs also exhibit uricosuric effects beneficial to management of gouty arthritis, increase plasma volume and cardiac output and work, stimulate respiration and respiratory alkalosis, and in large doses may cause hyperglycemia. Nonsteroidal agents are distinguished from true steroid agents, such as cortisone (cortisol), prednisone, triamcinolone, or methylprednisolone, and from the opiate-derived analgesics such as codeine, oxycodone, morphine sulfate, and meperidine. Table 1 lists representative NSAIDs grouped by chemical classification. BENEFITS AND RISKS The NSAIDs offer an impressive array of benefits to physical therapy patients, particularly as analgesic and anti-inflammatory agents, and are first-line drug choices for treatment of mild to moderate pain, soft tissue injury, osteoarthritis, gout, and inflammatory rheumatic disorders. However, their usage is associated with adverse effects of notable implication 356 Journal of Orthopaedic & Sports Physical Therapy

2 TABLE 1. Representative nonsteroidal anti-inflammatory agents (NSAIDs). NSAID Half Life (h) Onset (min) Comments Salicylates Aspirin (ASA)* Prototypical NSAID Diflunisal (Dolobid)* Salsalate (Disalcid, others) Acetic acid derivatives Etodolac (Lodine, Tolmetin) gastrointestinal tolerance Indomethacin (Indocin) potency, toxicity Ketoralac/Toradol analgesia effect Sulindac (Clinoril) Less potency and less toxicity than indomethacin Tolmetin (Tolectin) patient tolerance Fenamic acids No clear advantages Meclofenamate (Meclomen) diarrhea Propionic acid derivatives patient tolerance Fenoprofen (Nalfon) gastrointestinal tolerance Flurbiprofen (Ansaid) gastrointestinal tolerance Ibuprofen (Motrin, others) gastrointestinal tolerance Ketoprofen (Orudis) gastrointestinal tolerance Naproxen (Anaprox, Naprosyn) gastrointestinal tolerance Oxaprozin (Daypro) Long acting Oxicam derivatives Piroxicam (Feldene) Long onset, long acting Cox-2 specific gastrointestinal irritation, potential platelet aggregation varies with agent Celecoxib (Celebrex) cardiovascular risk than rofecoxib Rofecoxib (Vioxx) No longer available Valdecoxib/(Bextra) Abbreviations:, increased relative to ASA;, decreased relative to ASA. * Exerts drug effect as active metabolite salicylic acid. Extensively studied for use in children (use in febrile viral illness precluded). to rehabilitation outcome, necessitating vigilant monitoring of patients at high risk and pharmacologically inclusive patient management. Therapists who treat and/or prescribe these medications must balance the benefits against potential risk factors when planning and discussing treatment with patients. NSAIDs have a tendency to produce adverse effects on multiple-organ systems, with the major shared toxic effects being gastrointestinal (GI) ulceration, acute renal failure, and bleeding events. Other possible side effects include dyspepsia, nausea, edema, fluid retention, aphthous ulceration, and delayed wound-healing. NSAIDs may produce central nervous system side effects, including tinnitus, dizziness, confusion, and stupor. NSAID adverse effects are presented in Table 2. Lichtenstein and Wolfe 33 state, Toxicity induced by NSAID is among the most common serious adverse drug events in the industrialized world. Approximately 13 of every 1000 patients with rheumatoid arthritis who take NSAIDs for 1 year have a serious GI complication. Moreover, 5% to 15% of patients with rheumatoid arthritis are expected to discontinue NSAID therapy because of dyspepsia within a 6-month period of treatment. 49 As many as 1.2% of the US population uses NSAIDs daily and at least hospitalizations, and 2000 deaths per year result from complications, such as hemorrhage and gastric ulcer perforation, of NSAID use. 46,49 Risk factors for NSAID-induced GI bleed (listed in Table 3) include prior peptic ulcer, concomitant use TABLE 2. Potential nonsteroidal anti-inflammatory agents (NSAIDs) adverse effects by system. System Gastrointestinal Renal Central nervous system Hematological Allergic reactions Adverse Effects Nausea, heartburn, dyspepsia, gastric ulcers, duodenal ulcers, perforations, bleeding complications Sodium retention, edema, hyperkalemia, acute failure, nephritic syndrome, papillary necrosis Tinnitus, sedation, dizziness Hemorrhage, anemia, COX-2 cardiovascular events Other NSAID- or salicylin-containing foods: apples, oranges, bananas CLINICAL COMMENTARY J Orthop Sports Phys Ther Volume 35 Number 6 June

3 TABLE 3. Identification of patients at high-risk and potential adverse effects. High-Risk Population/ Condition Patient factors: increasing age, female sex, age 85 y History of peptic ulcer Low serum albumen Concomitant use of multiple antithrombotic agents Concomitant use of other NSAIDs or steroid agents, increasing NSAID dose, new NSAID user Hypovolemic states, renal impairment due to age, atherosclerosis, hypertensiverenal disease, or other intrinsic renal disease Adverse Affect Slowed metabolism and elevated tissue levels of more lipid-soluble drugs Repeat ulceration and GI hemorrhage Elevated serum NSAID levels and possible overdosage Hemorrhage GI injury, gastric hemorrhage, or initiation of GI ulceration Renal failure, impairment of glomerular filtration, acute renal failure, edema, interstitial nephritis, papillary necrosis, chronic renal failure, and hyperkalemia Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal antiinflammatory drug. TABLE 4. Adverse effect preventative measures. Alternatives to NSAIDs in osteoarthritis 1. Physical therapy 2. Behavior modification 3. Joint protection 4. Exercise 5. Weight loss 6. Acetaminophen Dosing to achieve minimum dose pain control Use for pain only as needed Selective use of safer NSAIDs first 1. Ibuprofen/motrin and others Avoid first choice use of long half-life agents. Abbreviations: NSAID, nonsteroidal anti-inflammatory drug. of other anticoagulant agents and/or steroid medications, and increasing patient age. Adults over the age of 60 taking NSAIDs have a 4- to 5-fold higher risk of GI bleeding or ulceration than younger individuals. In elderly patients and those with a history of NSAID-induced ulcers, traditional nonselective NSAIDs should be used with caution, usually in lower dose, if at all. NSAIDs are associated with renal toxicity, including azotemia and proteinuria, and renal failure requiring hospitalization, and should be avoided in persons with, or at risk for, renal disease. The appearance of adverse NSAID effects is typically dose related; therefore, the minimum dose required for pain relief, or other desired effects, should be sought by the monitoring or prescribing therapist. The merit of minimal-dose therapy is demonstrated by The Physicians Health Study Research Group, 45 which reported that there was no statistically significant risk in a minimal-dosage aspirin regimen ( 325 mg/d) as used for thromboprophylaxis. Methods of reducing risk to patients are listed in Table 4. NSAIDs CATEGORIES Aspirin, as acetylsalicylic acid, the archetypal NSAID agent, has been recognized for its pharmaceutical properties for centuries. It was first commercially marketed as Aspirin in 1899 by Friedrich Bayer & Co of Germany. The pharmacology of aspirin is quite consistent with that of other NSAIDs and aspirin remains the prototype for comparison of the efficacy and safety of newer medications in the class. Aspirin continues to be the first-line drug for a variety of conditions, including mild pain, fever, osteoarthritis, rheumatoid arthritis, stroke prevention therapy, and potential reduction of prostate cancer incidence. 33 Other NSAIDs differ from aspirin in modified pharmacokinetics, duration of action, and patient tolerance, but overall efficacy is very similar. Ciccone 15 comments that, The principal difference between aspirin and the newer NSAID is cost. Acetaminophen (Tylenol) is not typically classified as an NSAID by virtue of its lacking an antiinflammatory effect, but, since 1995, it has been recognized as the first-line agent (replacing aspirin) for treatment of osteoarthritis by the American College of Rheumatology. In comparing acetaminophen to other OTC medications, Lonner 34 reports, Given orally in divided doses of 4000 mg/d (the maximum recommended dosage given was 1000 mg every 4 to 6 hours), acetaminophen is as beneficial as ibuprofen and naproxen in reducing the pain of osteoarthritis and enhancing joint function. Acetaminophen is primarily centrally acting yet exerts its analgesic and antipyretic effects peripherally by weak inhibition of both isoforms of cyclooxygenase through an unknown mechanism. 16 Both acetaminophen and NSAIDs provide symptomatic relief only; they do not alter joint disease progression. Simon 43 notes, Unfortunately, NSAID use has not been shown to have long-term beneficial effects on the natural history of inflammatory diseases. Acetaminophen does not inhibit prostaglandin synthesis in peripheral tissues and consequently lacks anti-inflammatory properties. In high dose or with chronic usage, acetaminophen is associated with hepatic toxicity and, with cumulative lifetime use, shows the same relationship to renal failure as aspirin. 11,22 The selection process between the 2 groups is therefore dependent upon safety profile and patient risk factors. Acetaminophen is the analgesic of choice where NSAID use is precluded by allergy or hypersensitivity. Much attention has been given to the selective cyclooxygenase 2 (COX-2) inhibitors (eg, Vioxx/ rofecoxib, Celebrex/celecoxib, and Bextra/ 358 J Orthop Sports Phys Ther Volume 35 Number 6 June 2005

4 valdecoxib). These agents were developed to provide NSAID benefits without affecting the GI mucosa, renal tissue, or platelet aggregation. When compared to traditional nonselective NSAIDs, such as naproxen and ibuprofen, selective COX-2 agents (coxibs) achieve equal pain relief while reducing upper-gi dyspeptic symptoms by 15%. 48 The Arthritis Pain Society 4 recently endorsed coxibs as the drug class of choice for the initial management of moderate to severe arthritis pain, although COX-2 selective agents cost considerably more than the nonselective NSAIDs. Studies considering the increased cost of the selective agents in relation to their improved safety profile suggest that these agents may eventually dominate the nonselective NSAID arthritic pain management strategy of treatment only if the cost per coxib tablet is reduced by nearly 90%. 44 Despite the important relative risk reduction in GI complications afforded by the coxibs, their absolute risk reduction, compared with nonselective NSAIDs, is only 1% for significant ulcer complications, while potentially introducing new problems. Spiegel et al 44 report, The enthusiasm for the coxibs may be somewhat tempered by data suggesting they are associated with a higher rate of cardiovascular events than the nonselective NSAIDs. Data from newer studies support this concern, which led to the recent withdrawal of refocoxib/vioxx from the marketplace. PHARMACODYNAMICS NSAIDs produce their diverse effects by interfering with the enzymatic biosynthetic effect of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) on arachidonic acid. Arachidonic acid is present on cell membranes throughout the body and acts as a substrate for prostaglandin, prostacyclin, and thromboxane synthesis. Prostaglandins and other arachidonic acid derivatives, including prostacyclin, thromboxane, and leukotrienes, are classed as eicosanoids, but are often included for convenience in the prostaglandin category. They are among the most biologically active substances known and account for the complex pharmacodynamics of the NSAIDs and their wide variety of effects in the body. A prostaglandin may exhibit differing effects at different sites and physiologic conditions. Prostaglandins are typically rapidly metabolized, local acting, and swiftly degraded in the lungs, preventing systemic arterial distribution. COX-1 COX-1 is constitutively present in virtually all tissues under normal conditions. Notably, the COX-1 isoform is found in the endoplasmic reticulum of prostaglandin-producing (PGE 2, PGG, PGI 2 ) cells of the blood vessels, stomach, and kidneys. 30 In the GI tract, COX-1 promotes synthesis of cytoprotective gastric mucus and bicarbonate, and support for gastric mucosal blood flow. In the renal system, COX-1 promotes vasodilation, resulting in increased renal perfusion. COX-1 functions as a physiologic housekeeping enzyme in most tissues, including the gastric mucosa and platelets. 33 Conventional NSAIDs that exert a COX-1 inhibitory effect will deplete the body of specific prostaglandins (PGI 2 and PGE 2 ) that, in healthy individuals, facilitate these normal maintenance purposes. An increasing body of evidence has established that inhibition of COX-1 results in adverse events such as GI irritation and damage, platelet dysfunction, and bronchospasm. 10 Lichtenstein and Wolfe 33 report that the role of COX-1 in protecting the gastroduodenal mucosa is supported by studies showing that, The greatest degree of damage is generally caused by NSAIDs that preferentially inhibit COX-1. Platelet aggregation during the early phases of clot formation is mediated by thromboxane A 2 (TxA 2 ) influence on platelet aggregation factor. NSAID inhibition of COX-1 impedes thromboxane A 2 biosynthesis and platelet aggregation, resulting in decreased thrombus formation, which is the rationale for daily prophylactic aspirin to reduce stroke or myocardial infarct risk. All NSAIDs produce this effect but not all NSAIDs are recommended for this purpose due to differing mechanisms of action. COX-2 COX-2 is typically not found on cell membranes under baseline conditions but is induced and upregulated by cytokines, such as interleukin-1 (IL-1), in the presence of cell stress or injury. Arachidonic acid is released from cell membranes in response to physical, chemical, hormonal, and bacterial or other stimuli. A synthesis of PGE 2 by COX-2 results in facilitation of the inflammatory response to injury, including pyresis, chemotaxis, pain modulation, and potentiation of bradykinen and histamine. COX-2 upregulation during inflammation is decreased by NSAIDs and the steroid medications, which inhibit these vascular and inflammatory responses. By interfering with the arachidonic acid cascade, both steroid and nonsteroidal agents will impede the action of various healing-scheme mediators, primarily inhibiting the substrate phase of inflammation. When looking at animal models of inflammation, COX-2 was found in multiple cell types in the joint, including synovial lining cells, fibroblast-like cells, vascular endothelial cells, infiltrating mononuclear cells, chondrocytes, and adjacent bone marrow. 40 Its enzymatic activity leads to biosynthesis of prostaglandins, including PGE 2 and prostacyclin (PGI 2 ). PGE 2 mediates pyresis, inflammation, and pain. Interestingly, PGE 2 does not produce pain itself, but hyperalgesia by sensitizing afferent C fibers. The CLINICAL COMMENTARY J Orthop Sports Phys Ther Volume 35 Number 6 June

5 prostacyclin PGI 2 is a vasodilator and inhibitor of platelet aggregation. 10 PGI 2 additionally functions to modulate the balance between its own inhibition of platelet aggregation and thromboxane-a 2 -enhanced platelet aggregation. Selective inhibition of COX-2 diminishes this PGI 2 -modulating effect, perturbing the equilibrium between TxA 2 thrombogenesis promotion versus PGI 2 thrombogenesis inhibition, resulting in an overall shift toward platelet aggregation and thrombus formation. COX-1 and COX-2 effects are summarized in Table 5. COX-2 SPECIFIC NSAIDs The discoveries of 2 COX isoforms led to the development of drug agents that preferentially target COX-2 with reduced COX-1 inhibition (eg, Lodine/ etodolac and Meclomen/meloxicam), and those that exclusively inhibit COX-2 (eg, Vioxx, Bextra, and Celebrex), with little or no effect on COX-1. The COX-2 preferential drugs have, in early studies, shown a favorable safety profile compared to nonselective NSAIDs. COX-2 specific agents exert an antipyretic, analgesic, and anti-inflammatory effect (PGE 2 ), but do not impede COX-1 facilitated (PGE 2 and PGI 2 ) platelet aggregation or gastric mucosa protective mechanisms. Clinical trials have shown that celecoxib is as effective as ibuprofen in both osteoarthritis and rheumatoid arthritis in reducing arthritic pain and inflammation. The use of celecoxib/celebrex is associated with a lower incidence of symptomatic ulcers and ulcer complications compared with conventional NSAIDs in non-aspirin users. 41,48 However, there is evidence that both COX-1 and COX-2 derived prostaglandins are involved in gastric cytoprotective mechanisms. 36,41,47 Recent studies describe the constitutive expression of COX-2 in healthy human and animal gastric mucosa. 36 Other studies demonstrate that inhibition of both COX-1 and COX-2 is required for gastric injury while taking NSAIDs. 47 Clinically, the frequency of gastric irritation or ulceration is lower, but not eliminated, with use of coxibs compared to nonselective NSAIDs. Coxibs, if prescribed, are used with caution in those persons with preexisting risk factors such as age or history of GI ulcers. The COX-2 specific drugs were initially expected to show parallel effects in the kidney, as in the gastric mucosa, wherein COX-2 inhibition would spare adverse effects on renal function. The COX-2-specific drugs, based on these findings, were thought to be useful, with caution, for those patients with renal disease, whereas, the nonselective NSAIDs are contraindicated. However, this has not proven to be the case, as both COX-1 and COX-2 were subsequently found to be present in the kidney in constitutive form. Overall, the same precautions for patients at risk for adverse renal effects apply to both the traditional nonselective NSAIDs and COX-2 selective NSAIDs. The presence of COX-1 and COX-2 in renal tissue accounts for the deleterious drug interaction of NSAIDs, with a variety of diuretic agents resulting in hypertension, potassium retention, and acid-base shift. COX-2 Specific Agent Risk Factors The Vioxx Gastrointestinal Outcomes Research Study (VIGOR), 9 which compared GI safety of naproxen with refecoxib, noted that COX-2 inhibition of PGI 2, without an effect on TxA 2 (COX-1), increased cardiovascular risk. 14,37 The VIGOR study postulates that the unimpeded action of TxA 2 in combination with inhibition of PGI 2 modulation may create an increase in platelet aggregation activity. 9 The Celecoxib Long-Term Arthritis Safety Study (CLASS), 42 in which patients who were allowed to take concomitant aspirin, a thromboxane inhibitor, showed no significant difference in cardiovascular event (myocardial infarction, stroke, and death). The CLASS study states there is question as to the applicability of this finding regarding celecoxib to the coxib class in general. The authors raise a cautionary flag about the risk of cardiovascular events with COX-2 inhibitors and suggest that further prospective trials are indicated (in part because the VIGOR study was designed to monitor GI safety rather than cardiovascular risk) to determine the magnitude of the risk. Fenn 19 reports The Food and Drug Administration analysis 18 of the VIGOR study also shows no overall safety advantage for rofecoxib compared with conventional NSAID, with fewer complicated upper-gi TABLE 5. COX-1 and COX-2 enzymatic products and physiological effects compared. COX-1 Gastrointestinal mucoprotection (PGE 2 and prostacyclin PGI 2 ) Enhanced platelet aggregation (thromboxane A 2 ) Renal homeostasis and vascular homeostasis: renal vasodilation, diuresis, NaCl/ water excretion (PGE 2 and PGI 2 ) Uterine function, embryo implantation (PGD 2 ) Regulation of sleep-wake cycle (GPD 2 ) and body temperature (PGE 2 ) COX-2 Pain, pyresis, chemotaxis, inflammation (PGE 2 ) Potentiation of histamine and bradykinen (PGE 2 ) Vasodilation and inhibition of platelet aggregation (prostacyclin PGI 2 ) Modulation of thromboxaneenhanced platelet aggregation versus prostacyclin inhibition of platelet aggregation (prostacyclin PGI 2 ) 360 J Orthop Sports Phys Ther Volume 35 Number 6 June 2005

6 events being offset by a highly statistically significant increase in serious thrombotic cardiovascular events. This precaution was born out by the recent voluntary worldwide withdrawal of Vioxx/rofecoxib by its manufacturer Merck & Co, Inc, in response to the Adenomatous Polyp Prevention on VIOXX trial (AP- PROVe). The trial, which was stopped (prior to publication) in September 2004, was designed to evaluate the efficacy of VIOXX in preventing recurrent colorectal polyps in patients with a history of colorectal adenomas. The APPROVe 35 study did show an increased risk for confirmed cardiovascular events, such as heart attack and stroke, beginning after 18 months of treatment in the patients taking Vioxx compared to those taking placebo. The results for the first 18 months of the APPROVe study did not show any increased risk of confirmed cardiovascular events on Vioxx. Some COX-2 specific medications have greater antithrombotic properties than others, and hemorrhagic and GI risk factors also appear to vary among available agents. 29 Kimmel 31 reported that rofecoxib was associated with higher odds of heart attack compared with older NSAIDs, but no evidence for an increased (heart attack) risk from celecoxib/ Celebrex, again suggesting differences within the class of COX-2 inhibitors. As a precaution, physical therapists should monitor for cardiovascular complications in patients taking COX-2-specific medications until the degree of risk is more clearly determined in future studies. NSAIDs AND WOUND HEALING NSAIDs are commonly used to reduce postinjury and postoperative pain and inflammation. By impeding COX-2 proinflammatory activity, NSAIDs would appear beneficial to resolution of tissue injury and inflammation. The overall result, however, has proven to be tissue specific. NSAIDs produce no alteration in epithelial regeneration, but induce a modest delay in muscle strain healing during the acute (substrate) phase of inflammation and delayed healing in gastric ulceration. 2 In a tendon-healing study, indomethacin/indocin showed little effect on total collagen synthesis and may have produced increased tensile strength in healing tendon during the proliferative phase. 12 Hamstring injuries treated by physical therapists with and without NSAID usage showed no difference in outcome. 38 Of concern to therapists is growing evidence of NSAID impairment of bone and cartilage healing. NSAIDs potentially increase the rate of nonunion and delay healing in those fractures that do unite. 23 Glassmann et al 25 investigated the effect of clinically relevant NSAID doses in patients with a spinal fusion and report a 5-fold increase in the rate of nonunion in patients taking ketoralac/toradol 30 mg every 6 to 8 hours, as needed for pain. A proposed mechanism for this bone-healing alteration is NSAID interference with endochondral ossification. A consensus of multiple data suggests that NSAIDs do produce a modest delay in healing during the acute inflammatory phase, with no long-term difference in healing outcome in epithelial, tendon, or ligament healing, but significant induced delay of bone healing and increased risk of nonunion. To provide the best environment for acute and chronic wound healing, therapists and surgeons should attempt to identify and correct any factors that may impede success. NSAID use provides increased comfort and reduced inflammation, which may enhance some therapy modalities; but this must be balanced with limited delay of soft-tissue healing progression, particularly during the first few days of the inflammatory process, and possible long-term detriment to bone healing. NSAIDS AND THROMBOPROPHYLAXIS All nonspecific NSAIDs inhibit both COX-1 and COX-2 to varying degrees, but by different mechanisms. Aspirin, uniquely, modifies both COX-1 and COX-2 by an irreversible mechanism. The duration of aspirin s effect is determined by the rate of biosynthetic replacement of COX-1 and COX All other NSAIDs similarly interfere with COX-1 and COX-2, but by a competitive, reversible mechanism, making duration of action a function of a particular agent s individual pharmacokinetic properties. Aspirin s distinctive pharmacological action on platelets produces greater therapeutic predictability, making it the recommended agent for thromboprophylaxis. Evidence is mounting that concomitant use of ibuprofen and aspirin antagonizes the platelet inhibition induced by aspirin. The concomitant administration of Tylenol or refecoxib/vioxx does not antagonize the antiplatelet effect of aspirin. 10 Careful assessment of patient OTC and prescription NSAID usage will assist therapists in recognizing potential drug interactions that may be deleterious to patients and complicate modality delivery. Patients should be advised to use aspirin only, and not the COX-2 selective agents or any other NSAID alone or in combination with aspirin, for thromboprophylaxis. PHARMACOKINETICS Clinical consideration of drug behavior and impact on the patient is divided into 4 categories: absorption, distribution, metabolism, and elimination. Absorption NSAIDs are typically lipid-soluble weak acids and are ideally suited for rapid absorption from the acidic stomach and duodenum. In this formulation, drugs CLINICAL COMMENTARY J Orthop Sports Phys Ther Volume 35 Number 6 June

7 tend to remain nonionized and lipophilic, and more quickly cross the cell membrane lipid bilayer 20 than do hydrophilic and ionized drugs, generally allowing more rapid onset of effect. After ingestion, most NSAIDs will exhibit an effect within 15 to 30 minutes. Fast-onset agents will tend to demonstrate a rapid offset and, conversely, slow-onset agents characteristically demonstrate slow offset. The time interval to perceived symptom relief varies with the rate of enzymatic breakdown of previously synthesized prostaglandins and the time required for the ingested drug agent to inhibit replacement. The onset time varies widely among agents and with respect to symptom etiology. Patients using rapid-onset agents, such as ibuprofen or aspirin, for acute pain may note relief within minutes or hours, whereas reduction of chronic arthritic pain and inflammation may require a week or more. Therapists should anticipate this onset lag and advise patients to allow sufficient time (a week or more) for symptom relief. Once in the bloodstream NSAIDs, except for aspirin, are heavily bound to plasma proteins. That portion of a drug which becomes attached to serum protein (usually albumin) is termed protein bound and is inactive because it is not available for cellular uptake; only the free nonprotein-bound drug fraction is active (bioavailable) to exert a therapeutic effect. Extensive protein binding (ibuprofen, for example, is 99% protein bound) indicates that larger doses will be necessary to achieve sufficient free-drug concentration to produce a desired effect. Of clinical importance, persons with decreased serum albumin, seen with alcoholic or viral (HAV, HBV, and HCV) liver disease, or extrinsic obstructive liver disorders, such as gallstones or postoperative constricture of the bile ducts, may demonstrate increased active serumdrug fractions. Diseases associated with hypoalbuminemia, such as rheumatoid arthritis, will also produce increased active serum concentrations of normally heavily protein-bound NSAIDs. Serum albumin levels are routinely recorded on standard serum chemistry lab tests, allowing the therapist to anticipate possible alteration in active-drug concentration and clinical effect. This is particularly important with OTC NSAID usage, where patient-generated dose schedules may not take such factors into consideration. Despite the high level of NSAID protein binding, a therapeutic effect is exerted by the constant dissociation of the drug from its binding protein and release as free or active fraction within the serum. As the free-drug fraction is metabolized, additional proteinbound drug dissociates, maintaining a constant ratio of active free agent to protein-bound agent. Increased drug doses further saturate albumin, so that the bound fraction eventually peaks, resulting in an increased free active fraction. As a result, the relationship of low-dose to high-dose drug effect may be nonlinear. This is seen with aspirin, where a modest additional dosage may yield a significant increase in therapeutic or toxic effect. The monitoring therapist must recognize that dosage change may produce a nonlinear response in symptom relief and doserelated adverse effects. Because of NSAIDs high protein affinity they may displace other more weakly protein-bound drugs, unintentionally increasing their free-drug concentration. 28 Warfarin (Coumadin), sulfonyl-urea hypoglycemic agents (Diabinese, Glucatrol, Micronase, etc), and methotrexate (Folex, Mexate, and Rheumatrex) are examples of drug agents encountered in physical therapy practice that are competitively displaced from their protein-binding sites by NSAIDs. 28 Dosage should be adjusted or concurrent administration of these 2 drug groups avoided. Distribution After absorption, NSAIDs are widely distributed throughout most body tissues. The distribution of NSAIDs to the synovial, muscle, and bone compartments is a function of serum concentration; there is no specialized tissue compartment affinity. An effective dose in proper regimen and duration must be taken for sufficient diffusion of the drug into connective tissue compartments typically targeted within the physical therapy patient population. This reinforces the necessity of patient counseling to ensure dosage schedule compliance. The therapeutic dose for ibuprofen, for example, is 2400 mg per day; but patients using ibuprofen on a self-prescribed basis often underdose themselves and do not achieve sufficient serum-drug concentration and adequate diffusion into connective tissues for therapeutic effect. Additionally, NSAIDs inhibit ongoing enzymatic production of inflammatory substances but do not remove or facilitate absorption of existing active prostaglandins. As a result, single-dose or short-dose regimens may provide negligible symptom relief due to the presence of onboard prostaglandin, continuing the pain or inflammatory effect even in the presence of diminished synthesis of new prostaglandin. Metabolism How much ingested NSAID survives the digestive system to render an effect, at what speed it does so, and the duration of effect is of practical concern: appointments can be scheduled for maximal patient compliance and capability. The liver is responsible for metabolism and bioconversion of NSAIDs. Nearly all pharmacotherapeutic agents are metabolized by hepatic cytochrome P450 isoenzymes. Drug effect, duration, and elimination will vary with the availability of these enzymes. Two or more drugs may 362 J Orthop Sports Phys Ther Volume 35 Number 6 June 2005

8 TABLE 6. Nonsteroidal anti-inflammatory drug (NSAID) interactions. Drug Affected NSAID Involved Interaction Oral coagulants: Warfarin, all NSAIDs, ADP inhibitors, (eg, clopidogrel/plavix) All Increased anticoagulant activity and risk of hemorrhage, damage to gastrointestinal mucosa Methotrexate All Bone marrow toxicity, renal failure, and hepatic dysfunction Antihypertensive agents: beta blockers Indomethacin and possibly others Hypertension: avoid all NSAIDs if possible Steroids All Possible increased gastrointestinal bleeding or ulceration Diuretics ACE inhibitor diuretics Indomethacin and others Reduction in diuretic effect, may exacerbate congestive heart failure Triamterene Indomethacin Increased nephrotoxicity Diuretics in general All Increased risk of renal failure Potassium sparing All Hyperkalemia Hypoglycemic agents Aspirin Increased hypoglycemic effects Digoxin All Increased digoxin levels Herbals: ginkgo biloba, feverfew, ginger, ginseng All Increased anticoagulant effect Journal of Orthopaedic & Sports Physical Therapy compete for the same P450 enzymes, potentially extending the drug effects due to limited isoenzyme supply, or 1 drug agent may upregulate a particular P450 enzyme, generating more rapid metabolism of a second medication also metabolized by the same isoenzyme. The cytochrome P450 isoenzymes used to metabolize drug agents are limited to a rather small group; medication interactions are not uncommon. When the clinician observes a drug effect being greater or less than anticipated, P450 isoenzyme interactions should be investigated. Standard pharmacology reference texts list specific isoenzymes within a drug agent s description, allowing the practitioner to investigate possible interactions. Table 6 lists the more common interactions of NSAIDs with other medications. A vexing problem for many orally administered medications is first-pass effect, in which the liver immediately renders significant metabolic degradation of a drug prior to target tissue delivery. First-pass effect may quickly neutralize a large percentage of the ingested drug. Among NSAIDs, only aspirin and diclofenac/voltaren undergo substantial first-pass effect and show an immediate reduction in active drug quantity following hepatic passage. Patients with hepatic dysfunction will, on an equal-dose basis, show elevated serum levels of aspirin and diclofenac compared to other NSAIDs. In these patients, dosages should be decreased to compensate for the risk of accidental overdosage and obviate possible impact to patient therapeutic ability. Integration of NSAID half-life data into modality selection permits planning for maximal drug benefit and minimized adverse impact on therapy. Half-life refers to the time required for hepatic clearance of one-half of the drug on board. This scheme of hepatic drug metabolism is referred to as first-order or concentration-independent kinetics. A 100-mg dose of a drug demonstrating a 4-hour half-life will be reduced to 50 mg in 4 hours, 25 mg in 8 hours, 12.5 mg in 12 hours, and so on. NSAIDs are often divided into 2 groups, based on either short or relatively long half-lives. Table 1 shows approximate half-lives of representative NSAIDs. Whether in singleor multiple-dose regimens, discontinuation of a medication does not change the half-life of the drug remaining in the serum. When using agents especially prone to significant GI disturbance, dyspepsia, or pronounced central nervous system effects (eg, indomethacin/indocin [half-life, 3 hours]), the clinician should consider both drug half-life and peak serum level (attained at 2 hours with Indocin) to avoid scheduling active therapy during periods of greatest patient compromise. All NSAIDs may cause GI discomfort (decreased by eating food prior to drug administration, which may delay therapeutic onset) and, especially in children, sedation or dizziness, which will greatly decrease patient rehabilitation capability. In the case of ibuprofen, peak serum concentrations are observed 1 to 2 hours following oral administration and its half-life is 2 hours. 28 Clinicians may therefore wish to provide treatment about 1 hour after drug ingestion, particularly when CLINICAL COMMENTARY J Orthop Sports Phys Ther Volume 35 Number 6 June

9 the patient uses ibuprofen on an as-needed basis. Ibuprofen and other medications with a short half-life also, as noted, demonstrate more rapid offset and re-emergence of symptoms. To avoid the problem of rapid drug offset prior to or during treatment, scheduling consideration should be given to patients using medications with relatively quick onset, short half-life, and frequent dosing, as opposed to longhalf-life, extended-dosage-interval drugs. Extended duration of action is a goal of pharmaceutical research demonstrated by the development of such NSAIDs as oxaprozin/daypro or piroxicam/feldene. Potential advantages in choosing these long-acting agents are greater compliance to dosage schedule and more gradual offset of action, balanced with a possible increase in adverse effects. A second hepatic drug metabolism scheme is zero-order or concentration-dependent kinetics. Zeroorder kinetics is encountered with NSAIDs and many other drugs in toxic overdosage scenarios, but is characteristic of the salicylates (aspirin and diflunisal/dolobid) at therapeutic drug concentration, creating a particular need for patient monitoring. The half-life of salicylic acid, the active metabolite of aspirin, is 2 to 3 hours in low dosage ( mg, single dose orally), wherein drug metabolism proceeds by first-order kinetics. But it is 15 to 30 hours at higher therapeutic doses, as are often used for anti-inflammatory effect, 34 owing to limited hepatic metabolism capability (cytochrome P450 isoenzyme), which creates a dose-dependent/zeroorder kinetics elimination scheme. In zero-order kinetics, no half-life exists; rather, a given amount (mg per hour), not percentage (half-life), of the drug is metabolized per unit time. For this reason, small incremental increases in aspirin dosage can create markedly disproportionate elevation of plasma levels as the liver becomes saturated with drug. Aspirin metabolism, half-life, and propensity to adverse effect or toxicity, therefore, vary in nonlinear relationship with increasing dosage. As a result, accurate monitoring of aspirin dosage is significant to both maintenance of therapeutic benefit and timely recognition of toxic effects. Rheumatologists at times use tinnitus, a reversible side effect of aspirin toxicity, as an indicator of ceiling therapeutic concentrations when treating arthritic disorders, particularly rheumatoid arthritis. The therapist should note the presence of tinnitus, along with headache, dizziness, fever, and mental status changes as a marker of aspirin toxicity. Overdose can cause the very symptoms that the patient set out to treat: headache and fever. A related pharmacokinetic consideration is steadystate concentration. NSAIDs produce greater beneficial effect when taken regularly in a dose schedule relationship that produces near constant plasma levels of the drug. The timing of dosage repetition is clinically important, because NSAIDs inhibit the production of COX-1 and COX-2 products, but do not actively promote elimination of inflammationmediating substances from the body. Proper regular dosing of NSAIDs is far more efficacious than sporadic. 4,5 When administered on a regular intermittent dosage (eg, 250 mg every 8 hours), the interdose drug concentration will rise and fall, but the drug will accumulate until the amount administered per unit time is equal to the amount eliminated per unit time. At steady-state, the cycle is repeated identically in each interval and the average plasma concentration is called the steady-state concentration. Steadystate is generally considered to be achieved after 4 doses, when administered at intervals equal to the drug s half-life. Conversation with the patient to ensure drug dose schedule compliance versus asneeded or irregular use allows more flexibility in treatment scheduling and modality delivery, with decreased associated serum-concentration-dependent drug effect or side-effect limitations. Understanding NSAID metabolism is also significant to antithrombotic effect. Aspirin s ability to inhibit platelet aggregation by suppression of thromboxane B 2 occurs 30 to 60 minutes after ingestion. As previously noted, this is an irreversible effect and platelets will remain inactive for the 7- to 10-day duration of their circulation life. 13 However, this effect is measurable for only 4 to 5 days after aspirin discontinuation because new platelets are constantly released into the circulation. Alteration of platelet aggregation leading to hemorrhagic events resulting in permanent disability are not uncommon in patients taking NSAIDs and may include GI bleeding, stroke, intracranial bleeding, hemorrhagic injury to the eye, and pulmonary events. 27 Clinically platelet disorders are evidenced more commonly by epistaxis, bleeding gums, ecchymosis, and petechiae, 17 whereas serum protein coagulopathies are more associated with deep bleeding and risk of hemarthrosis. Aspirin has little effect in terms of bruising and there is a paucity of reported cases of hemarthrosis resulting from aspirin therapy alone. 10,20 The risk of hemorrhage increases with patient age, especially after age 60, and in patients taking multiple concurrent anticoagulant medications. 20 Spontaneous hemarthrosis has been reported with aspirin used in combination with clopidogrel/plavix, an ADP receptor antagonist also used to decrease thrombogenesis. 24 The clinician considering vigorous regimens or deep modalities 5 must distinguish NSAID inhibition of platelet aggregation from coagulopathies or the effects of antithrombotic anticoagulant medications such as Warfarin/Coumadin and heparin. Specific 364 J Orthop Sports Phys Ther Volume 35 Number 6 June 2005

10 tests for platelet function are less frequently ordered than lab studies measuring serum-clotting protein function. The prothrombin time and partial thromboplastin time are lab tests used to assess serum protein coagulopathies, for perioperative evaluation of serum-clotting protein function, and to monitor anticoagulant dosage in postsurgical conditions, myocardial infarct, or patients with a cerebral vascular accident. The partial thromboplastin time and prothrombin time tests do not give information as to platelet number or aggregation function. Platelet effectiveness is assessed both by platelet count and aggregation activity. Normal platelet count should be above per ml. This measurement is part of the routine complete blood count (CBC) lab test. Thrombocytopenia may become clinically evident, by physical signs previously noted, at platelet levels less than to per ml. Platelet function is measured by the Ivy or Duke bleedingtime tests. Clinical correlation between bleeding-test results and aspirin or other NSAID effects may be variable. A newer mechanized method of quantifying platelet aggregation function is derived in a manner analogous to bleeding-time tests. The instrument draws blood from the tube and simulates in vivo vascular injury, then records the time required for platelet attachment, activation, aggregation, and building of a platelet plug at the recording aperture of the instrument. 19 Elimination After hepatic biotransformation, NSAIDs are eliminated by renal excretion. This process follows the typical elimination scheme of other lipid-soluble drugs. As with most pharmaceutical agents, NSAIDs are converted by hepatic cytochrome P450 isoenzymes to hydrophilic substances that are more easily excreted in the urine. Alterations in urine ph can affect the level of ionized or nonionized drug residue and, therefore, rates of elimination. Salicylates are more rapidly cleared at alkaline ph levels. At ph 8.0 salicylates are cleared at about 4 times the rate they are at ph 6.0. The duration of action of NSAIDs, like other renal-excreted drugs, can be somewhat extended in the presence of acidic foods, which favor the nonionized lipid-soluble drug condition, and the duration of action shortened with alkaline foods that favor ionization and water solubility. In a more acidic environment, the weak acid NSAIDs remain nonionized and do not remain with the water-soluble renal filtrate, but are reabsorbed into the systemic circulation. The rate of elimination also varies with urine output. Higher urine flow rates decrease tubular reabsorption, while decreased flow rates increase reabsorption and systemic retention of the drug agent. Discussion regarding patient dietary habits can allow enhanced therapeutic delivery and outcomes by modifying elimination rates of prescribed medications, without altering the prescription regimen. ALGORITHMS OF SELECTION The extensive variety of NSAIDs on the market raises the question of prescribing algorithms identifying a drug of choice and second- or third-choice agents. Nahlik 32 states, All currently marketed NSAIDs have been extensively studied in clinical trials and there is little evidence to suggest that one is significantly more effective than another for the variety of rheumatic disorders for which they are generally prescribed. Based on the evidence to date, all NSAIDs, when given in equipotent doses, have comparable efficacy. Given this equivalence, in choosing a particular NSAID for an individual patient, tolerability profiles remain potential ways in which it may be possible to differentiate between different drugs. Practitioners tend to select between similar drugs on the basis of 3 parameters: patient compliance, cost to patient, and patient preference. Safavi and Hayward 39 observe,...preferences in NSAID prescribing were mainly determined by which drugs enhanced compliance or were used by other prescribing personnel (the traditional choice ), with cost to the patient being less an influence in selection. OTC drugs, such as aspirin, ibuprofen, and naproxen, are first-line drugs based on cost and availability. Nevertheless, some consistent themes are found in multiple studies using differing methodologies and settings. Drugs with longer half-lives, such as piroxicam, ketoprofin, and azapropazone, are associated with the highest risk for adverse effect and, conversely, those agents with shorter half-lives demonstrate lower risk. Ibuprofen, for example, with a half-life of 2 hours, most consistently shows lower risk for adverse GI events in standard dosage ( 1500 mg/d), though in higher dosage ( mg/d) the risk becomes comparable to other NSAIDs taken at standard dosage. A simplified method of drug agent selection is presented in Table 7. The effect of a given NSAID will vary among individual patients, sometimes leading to trial of several different agents in an effort to obtain the best therapeutic effect. NSAIDs are classified by chemical structure, allowing products of differing chemical families to be selected as replacements for ineffective agents. In clinical practice, 7 to 10 days is generally long enough (with the exception of specific longonset agents such as piroxicam/feldene) to ascertain the effect of a given drug. 28 Patients should be encouraged to continue taking a trial medication at least that long before concluding ineffectiveness. Once an effective drug is identified, the dosage may be gradually reduced to find the lowest effective dose for the patient. CLINICAL COMMENTARY J Orthop Sports Phys Ther Volume 35 Number 6 June