Pharmacology in Rehabilitation_ Nonsteroidal Anti-Inflammato

Pharmacology in Rehabilitation:Nonsteroidal Anti-inflammatory AgentsRoss E. Biederman, DPM1

Nonsteroidal anti-inflammatory agents (NSAIDs) are the most commonly encountered over-the-counter (OTC) and prescription medications in physical therapy practice. Worldwide, over 73 000000 prescriptions for nonsteroidal agents are written yearly. NSAIDs produce a wide range ofbeneficial effects to the physical therapy patient, enhancing the outcome of treatment. Helpfuleffects of NSAIDs include analgesia, antipyretic, anti-inflammatory, and antithrombotic properties.However, NSAIDs are also associated with frequent and significant side effects that are deleteriousto 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 theindividual pharmacokinetics of specific preparations will help the therapist to screen patients forpotential side effects, develop more effective plans of care, and, where allowed, effectively andsafely prescribe NSAIDs. J Orthop Sports Phys Ther 2005;35:356-367.

Key Words: aspirin, COX-2 inhibitors, ibuprofen, NSAID, pharmacokinetics

The Guide to Physical Therapist Practice3 identifies clinicalpharmacology as an essential component of appropriatepatient monitoring, modality delivery, and communicationamong medical professionals. The prescription-drug–writingprivileges exercised by select military therapists and the

evolution of the physical therapy profession promote consideration of anexpanded pharmacological role in physical therapy practice. Whetherthe individual practitioner acts to monitor or prescribe drug agents, theimportance of a pharmacologically integrated approach to comprehen-sive patient management cannot be underestimated.

By far the most frequently encountered and/or prescribed drugagents in physical therapy practice are the nonsteroidal anti-inflammatory agents (NSAIDs). A sense of magnitude is gained byrecognizing that NSAIDs are, in both their prescription and over-the-counter (OTC) forms, the most commonly utilized drug agents in theUnited States, and that worldwide over 73 000 000 prescriptions arewritten yearly.43 Of patients seeing physical therapists, 25% to 40% aretaking prescription anti-inflammatory agents with about 40% of thoseusing multiple NSAIDs concomitantly.6,7 Using data from a multicenterphysical therapy study, Boissonnault and Meek8 report that 78.6% ofpatients seen for treatment had used aspirin or other OTC anti-inflammatory agents within the prior week.

1Diplomat, American Board of Podiatric Surgery, San Francisco, CA; Professor, Physical TherapyDepartment, Azusa Pacific University, Azusa, CA.I affirm that I have no personal associations, financial affiliations or involvement with any commercialorganization 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 91702. E-mail: [email protected]

NSAIDs are defined as a diversegroup of drugs with the sharedability to (1) relieve pain, (2) de-crease inflammation, (3) decreaseelevated body temperature, and(4) decrease blood clotting (non-selective NSAIDs only) by inhibi-tion of platelet aggregation.15

Traditional nonselective NSAIDsare used to prevent recurrentstroke26 and evidence is growingfor the ability of select NSAIDs todelay progression of Alzheimer’sDisease.1 NSAIDs also exhibituricosuric effects beneficial tomanagement of gouty arthritis, in-crease plasma volume and cardiacoutput and work, stimulate respira-tion and respiratory alkalosis, andin large doses may causehyperglycemia. Nonsteroidalagents are distinguished from truesteroid agents, such as cortisone(cortisol), prednisone, triamcino-lone, or methylprednisolone, andfrom the opiate-derived analgesicssuch as codeine, oxycodone, mor-phine sulfate, and meperidine.Table 1 lists representative NSAIDsgrouped by chemical classification.

BENEFITS AND RISKS

The NSAIDs offer an impressivearray of benefits to physicaltherapy patients, particularly as an-algesic and anti-inflammatoryagents, and are first-line drugchoices for treatment of mild tomoderate pain, soft tissue injury,osteoarthritis, gout, and inflamma-tory rheumatic disorders. However,their usage is associated with ad-verse effects of notable implication

356 Journal of Orthopaedic & Sports Physical Therapy

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TABLE 1. Representative nonsteroidal anti-inflammatory agents (NSAIDs).

NSAID Half Life (h) Onset (min) Comments

SalicylatesAspirin (ASA)*† 0.25 10-30 Prototypical NSAIDDiflunisal (Dolobid)* 16.00 30-60Salsalate (Disalcid, others) 2.00-3.00 10-30

Acetic acid derivativesEtodolac (Lodine, Tolmetin) 3.00-11.00 30 ↑ gastrointestinal toleranceIndomethacin (Indocin) 4.50 30 ↑ potency, ↑ toxicityKetoralac/Toradol 2.50 30-60 ↑ analgesia effectSulindac (Clinoril) 8.00 60 Less potency and less toxicity

than indomethacinTolmetin (Tolectin)† 2.00-5.00 10-30 ↑ patient tolerance

Fenamic acids No clear advantagesMeclofenamate (Meclomen) 2.00 60-120 ↑ diarrhea

Propionic acid derivatives ↑ patient toleranceFenoprofen (Nalfon) 3.00 30 ↑ gastrointestinal toleranceFlurbiprofen (Ansaid) 3.80 60 ↑ gastrointestinal toleranceIbuprofen (Motrin, others) 2.00 10-30 ↑ gastrointestinal toleranceKetoprofen (Orudis) 2.00-4.00 30 ↑ gastrointestinal toleranceNaproxen† (Anaprox, Naprosyn) 13.00 60-120 ↑ gastrointestinal toleranceOxaprozin (Daypro) 58.00 60 Long acting

Oxicam derivativesPiroxicam (Feldene) 50.00 15-30 Long onset, long acting

Cox-2 specific ↓ gastrointestinal irritation,potential ↑ platelet aggrega-tion varies with agent

Celecoxib (Celebrex) 11.00 30-60 ↓ cardiovascular risk thanrofecoxib

Rofecoxib (Vioxx) 24.00 45 No longer availableValdecoxib/(Bextra) 8.00-11.00 60

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 moni-toring of patients at high risk and pharmacologicallyinclusive patient management. Therapists who treatand/or prescribe these medications must balance thebenefits against potential risk factors when planningand discussing treatment with patients.

NSAIDs have a tendency to produce adverse effectson multiple-organ systems, with the major sharedtoxic effects being gastrointestinal (GI) ulceration,acute renal failure, and bleeding events. Other pos-sible side effects include dyspepsia, nausea, edema,fluid retention, aphthous ulceration, and delayedwound-healing. NSAIDs may produce central nervoussystem side effects, including tinnitus, dizziness, con-fusion, and stupor. NSAID adverse effects are pre-sented in Table 2.

Lichtenstein and Wolfe33 state, ‘‘Toxicity inducedby NSAID is among the most common serious ad-verse drug events in the industrialized world.’’ Ap-proximately 13 of every 1000 patients withrheumatoid arthritis who take NSAIDs for 1 year havea serious GI complication. Moreover, 5% to 15% ofpatients with rheumatoid arthritis are expected todiscontinue NSAID therapy because of dyspepsia

within a 6-month period of treatment.49 As many as1.2% of the US population uses NSAIDs daily and atleast 20 000 hospitalizations, and 2000 deaths peryear result from complications, such as hemorrhageand gastric ulcer perforation, of NSAID use.46,49

Risk factors for NSAID-induced GI bleed (listed inTable 3) include prior peptic ulcer, concomitant use

TABLE 2. Potential nonsteroidal anti-inflammatory agents(NSAIDs) adverse effects by system.

System Adverse Effects

Gastrointestinal Nausea, heartburn, dyspepsia, gastriculcers, duodenal ulcers, perforations,bleeding complications

Renal Sodium retention, edema,hyperkalemia, acute failure, nephriticsyndrome, papillary necrosis

Central nervoussystem

Tinnitus, sedation, dizziness

Hematological Hemorrhage, anemia, COX-2 cardio-vascular events

Allergic reactions Other NSAID- or salicylin-containingfoods: apples, oranges, bananas

J Orthop Sports Phys Ther • Volume 35 • Number 6 • June 2005 357

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TABLE 3. Identification of patients at high-risk and potentialadverse effects.

High-Risk Population/Condition Adverse Affect

Patient factors: increasing age,female sex, age � 85 y

Slowed metabolism and el-evated tissue levels of morelipid-soluble drugs

History of peptic ulcer Repeat ulceration and GIhemorrhage

Low serum albumen Elevated serum NSAID levelsand possible overdosage

Concomitant use of multipleantithrombotic agents

Hemorrhage

Concomitant use of otherNSAIDs or steroid agents,increasing NSAID dose, newNSAID user

GI injury, gastric hemorrhage,or initiation of GI ulceration

Hypovolemic states, renal im-pairment due to age, athero-sclerosis, hypertensiverenaldisease, or other intrinsicrenal disease

Renal failure, impairment ofglomerular filtration, acuterenal failure, edema, intersti-tial nephritis, papillary ne-crosis, chronic renal failure,and hyperkalemia

Abbreviations: GI, gastrointestinal; NSAID, nonsteroidal anti-inflammatory drug.

TABLE 4. Adverse effect preventative measures.

Alternatives to NSAIDs in osteoarthritis1. Physical therapy2. Behavior modification3. Joint protection4. Exercise5. Weight loss6. Acetaminophen

Dosing to achieve minimum dose pain controlUse for pain only as needed

Selective use of safer NSAIDs first1. 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 medica-tions, and increasing patient age. Adults over the ageof 60 taking NSAIDs have a 4- to 5-fold higher risk ofGI bleeding or ulceration than younger individuals.In elderly patients and those with a history ofNSAID-induced ulcers, traditional nonselectiveNSAIDs should be used with caution, usually in lowerdose, if at all. NSAIDs are associated with renaltoxicity, including azotemia and proteinuria, andrenal failure requiring hospitalization, and should beavoided in persons with, or at risk for, renal disease.The appearance of adverse NSAID effects is typicallydose related; therefore, the minimum dose requiredfor pain relief, or other desired effects, should besought by the monitoring or prescribing therapist.The merit of minimal-dose therapy is demonstratedby The Physicians’ Health Study Research Group,45

which reported that there was no statistically signifi-cant risk in a minimal-dosage aspirin regimen (�325mg/d) as used for thromboprophylaxis. Methods ofreducing risk to patients are listed in Table 4.

NSAIDs CATEGORIESAspirin, as acetylsalicylic acid, the archetypal

NSAID agent, has been recognized for its pharmaceu-tical properties for centuries. It was first commerciallymarketed as Aspirin in 1899 by Friedrich Bayer & Coof Germany. The pharmacology of aspirin is quiteconsistent with that of other NSAIDs and aspirinremains the prototype for comparison of the efficacyand safety of newer medications in the class. Aspirincontinues to be the first-line drug for a variety ofconditions, including mild pain, fever, osteoarthritis,rheumatoid arthritis, stroke prevention therapy, andpotential reduction of prostate cancer incidence.33

Other NSAIDs differ from aspirin in modifiedpharmacokinetics, duration of action, and patienttolerance, but overall efficacy is very similar. Cic-cone15 comments that, ‘‘The principal differencebetween aspirin and the newer NSAID is cost.’’

Acetaminophen (Tylenol) is not typically classifiedas an NSAID by virtue of its lacking an anti-inflammatory effect, but, since 1995, it has beenrecognized as the first-line agent (replacing aspirin)for treatment of osteoarthritis by the American Col-lege of Rheumatology. In comparing acetaminophento other OTC medications, Lonner34 reports, ‘‘Givenorally in divided doses of 4000 mg/d (the maximumrecommended dosage given was 1000 mg every 4 to 6hours), acetaminophen is as beneficial as ibuprofenand naproxen in reducing the pain of osteoarthritisand enhancing joint function.’’

Acetaminophen is primarily centrally acting yetexerts its analgesic and antipyretic effects peripherallyby weak inhibition of both isoforms of cyclo-oxygenase through an unknown mechanism.16 Bothacetaminophen and NSAIDs provide symptomaticrelief only; they do not alter joint disease progression.Simon43 notes, ‘‘Unfortunately, NSAID use has notbeen shown to have long-term beneficial effects onthe natural history of inflammatory diseases.’’

Acetaminophen does not inhibit prostaglandin syn-thesis in peripheral tissues and consequently lacksanti-inflammatory properties. In high dose or withchronic usage, acetaminophen is associated withhepatic toxicity and, with cumulative lifetime use,shows the same relationship to renal failure asaspirin.11,22 The selection process between the 2groups is therefore dependent upon safety profileand patient risk factors. Acetaminophen is the analge-sic of choice where NSAID use is precluded by allergyor hypersensitivity.

Much attention has been given to the selectivecyclooxygenase 2 (COX-2) inhibitors (eg, Vioxx/rofecoxib, Celebrex/celecoxib, and Bextra/

358 J Orthop Sports Phys Ther • Volume 35 • Number 6 • June 2005

valdecoxib). These agents were developed to provideNSAID benefits without affecting the GI mucosa,renal tissue, or platelet aggregation. When comparedto traditional nonselective NSAIDs, such as naproxenand ibuprofen, selective COX-2 agents (coxibs)achieve equal pain relief while reducing upper-GIdyspeptic symptoms by 15%.48 The Arthritis PainSociety4 recently endorsed coxibs as the drug class ofchoice for the initial management of moderate tosevere arthritis pain, although COX-2 selective agentscost considerably more than the nonselective NSAIDs.Studies considering the increased cost of the selectiveagents in relation to their improved safety profilesuggest that these agents may eventually dominatethe nonselective NSAID arthritic pain managementstrategy of treatment only if the cost per coxib tabletis reduced by nearly 90%.44

Despite the important relative risk reduction in GIcomplications afforded by the coxibs, their absoluterisk reduction, compared with nonselective NSAIDs,is only 1% for significant ulcer complications, whilepotentially introducing new problems. Spiegel et al44

report, ‘‘The enthusiasm for the coxibs may besomewhat tempered by data suggesting they areassociated with a higher rate of cardiovascular eventsthan the nonselective NSAIDs.’’ Data from newerstudies support this concern, which led to the recentwithdrawal of refocoxib/Vioxx from the marketplace.

PHARMACODYNAMICS

NSAIDs produce their diverse effects by interferingwith the enzymatic biosynthetic effect ofcyclooxygenase-1 (COX-1) and cyclooxygenase-2(COX-2) on arachidonic acid. Arachidonic acid ispresent on cell membranes throughout the body andacts as a substrate for prostaglandin, prostacyclin, andthromboxane synthesis. Prostaglandins and otherarachidonic acid derivatives, including prostacyclin,thromboxane, and leukotrienes, are classed aseicosanoids, but are often included for conveniencein the prostaglandin category. They are among themost biologically active substances known and ac-count for the complex pharmacodynamics of theNSAIDs and their wide variety of effects in the body.A prostaglandin may exhibit differing effects at differ-ent sites and physiologic conditions. Prostaglandinsare typically rapidly metabolized, local acting, andswiftly degraded in the lungs, preventing systemicarterial distribution.

COX-1

COX-1 is constitutively present in virtually all tis-sues under normal conditions. Notably, the COX-1isoform is found in the endoplasmic reticulum ofprostaglandin-producing (PGE2, PGG, PGI2) cells ofthe blood vessels, stomach, and kidneys.30 In the GI

tract, COX-1 promotes synthesis of cytoprotectivegastric mucus and bicarbonate, and support forgastric mucosal blood flow. In the renal system,COX-1 promotes vasodilation, resulting in increasedrenal perfusion. COX-1 functions as a physiologic‘‘housekeeping’’ enzyme in most tissues, includingthe gastric mucosa and platelets.33 ConventionalNSAIDs that exert a COX-1 inhibitory effect willdeplete the body of specific prostaglandins (PGI2 andPGE2) that, in healthy individuals, facilitate thesenormal maintenance purposes. An increasing body ofevidence has established that inhibition of COX-1results in adverse events such as GI irritation anddamage, platelet dysfunction, and bronchospasm.10

Lichtenstein and Wolfe33 report that the role ofCOX-1 in protecting the gastroduodenal mucosa issupported by studies showing that, ‘‘The greatestdegree of damage is generally caused by NSAIDs thatpreferentially inhibit COX-1.’’

Platelet aggregation during the early phases of clotformation is mediated by thromboxane A2 (TxA2)influence on platelet aggregation factor. NSAID inhi-bition of COX-1 impedes thromboxane A2

biosynthesis and platelet aggregation, resulting indecreased thrombus formation, which is the rationalefor daily prophylactic aspirin to reduce stroke ormyocardial infarct risk. All NSAIDs produce thiseffect but not all NSAIDs are recommended for thispurpose due to differing mechanisms of action.

COX-2COX-2 is typically not found on cell membranes

under baseline conditions but is induced andupregulated by cytokines, such as interleukin-1 (IL-1),in the presence of cell stress or injury. Arachidonicacid is released from cell membranes in response tophysical, chemical, hormonal, and bacterial or otherstimuli. A synthesis of PGE2 by COX-2 results infacilitation of the inflammatory response to injury,including pyresis, chemotaxis, pain modulation, andpotentiation of bradykinen and histamine. COX-2upregulation during inflammation is decreased byNSAIDs and the steroid medications, which inhibitthese vascular and inflammatory responses. By inter-fering with the arachidonic acid cascade, both steroidand nonsteroidal agents will impede the action ofvarious healing-scheme mediators, primarily inhibit-ing 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 mononuclearcells, chondrocytes, and adjacent bone marrow.40 Itsenzymatic activity leads to biosynthesis ofprostaglandins, including PGE2 and prostacyclin(PGI2). PGE2 mediates pyresis, inflammation, andpain. Interestingly, PGE2 does not produce pain itself,but hyperalgesia by sensitizing afferent C fibers. The


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prostacyclin PGI2 is a vasodilator and inhibitor ofplatelet aggregation.10 PGI2 additionally functions tomodulate the balance between its own inhibition ofplatelet aggregation and thromboxane-A2-enhancedplatelet aggregation. Selective inhibition of COX-2diminishes this PGI2-modulating effect, perturbingthe equilibrium between TxA2 thrombogenesis pro-motion versus PGI2 thrombogenesis inhibition, result-ing in an overall shift toward platelet aggregation andthrombus formation. COX-1 and COX-2 effects aresummarized in Table 5.

COX-2 SPECIFIC NSAIDsThe discoveries of 2 COX isoforms led to the

development of drug agents that preferentially targetCOX-2 with reduced COX-1 inhibition (eg, Lodine/etodolac and Meclomen/meloxicam), and those thatexclusively inhibit COX-2 (eg, Vioxx, Bextra, andCelebrex), with little or no effect on COX-1. TheCOX-2 preferential drugs have, in early studies,shown a favorable safety profile compared to nonse-lective NSAIDs. COX-2 specific agents exert anantipyretic, analgesic, and anti-inflammatory effect(PGE2), but do not impede COX-1–facilitated (PGE2

and PGI2) platelet aggregation or gastric mucosaprotective mechanisms.

Clinical trials have shown that celecoxib is aseffective as ibuprofen in both osteoarthritis andrheumatoid arthritis in reducing arthritic pain andinflammation. The use of celecoxib/Celebrex is asso-ciated with a lower incidence of symptomatic ulcersand ulcer complications compared with conventionalNSAIDs in non-aspirin users.41,48 However, there isevidence that both COX-1– and COX-2–derivedprostaglandins are involved in gastric cytoprotectivemechanisms.36,41,47 Recent studies describe the consti-tutive expression of COX-2 in healthy human andanimal gastric mucosa.36 Other studies demonstratethat inhibition of both COX-1 and COX-2 is requiredfor gastric injury while taking NSAIDs.47 Clinically,the frequency of gastric irritation or ulceration islower, but not eliminated, with use of coxibs com-pared to nonselective NSAIDs. Coxibs, if prescribed,are used with caution in those persons with pre-existing risk factors such as age or history of GIulcers.

The COX-2–specific drugs were initially expectedto show parallel effects in the kidney, as in the gastricmucosa, wherein COX-2 inhibition would spare ad-verse effects on renal function. The COX-2-specificdrugs, based on these findings, were thought to beuseful, with caution, for those patients with renaldisease, whereas, the nonselective NSAIDs arecontraindicated. However, this has not proven to bethe case, as both COX-1 and COX-2 were subse-quently found to be present in the kidney in constitu-tive form. Overall, the same precautions for patientsat risk for adverse renal effects apply to both the

traditional nonselective NSAIDs and COX-2 selectiveNSAIDs. The presence of COX-1 and COX-2 in renaltissue accounts for the deleterious drug interaction ofNSAIDs, with a variety of diuretic agents resulting inhypertension, potassium retention, and acid-baseshift.

COX-2 Specific Agent Risk Factors

The Vioxx Gastrointestinal Outcomes ResearchStudy (VIGOR),9 which compared GI safety of na-proxen with refecoxib, noted that COX-2 inhibitionof PGI2, without an effect on TxA2 (COX-1), in-creased cardiovascular risk.14,37 The VIGOR studypostulates that the unimpeded action of TxA2 incombination with inhibition of PGI2 modulation maycreate an increase in platelet aggregation activity.9

The Celecoxib Long-Term Arthritis Safety Study(CLASS),42 in which patients who were allowed totake concomitant aspirin, a thromboxane inhibitor,showed no significant difference in cardiovascularevent (myocardial infarction, stroke, and death). TheCLASS study states there is question as to theapplicability of this finding regarding celecoxib to thecoxib class in general. The authors raise a cautionaryflag about the risk of cardiovascular events withCOX-2 inhibitors and suggest that further prospectivetrials are indicated (in part because the VIGOR studywas designed to monitor GI safety rather than cardio-vascular risk) to determine the magnitude of the risk.Fenn19 reports ‘‘The Food and Drug Administrationanalysis18 of the VIGOR study also shows no overallsafety advantage for rofecoxib compared with conven-tional NSAID, with fewer complicated upper-GI

TABLE 5. COX-1 and COX-2 enzymatic products and physi-ological effects compared.

COX-1 COX-2

Gastrointestinal mucoprotec-tion (PGE2 and prostacyclinPGI2)

Pain, pyresis, chemotaxis, in-flammation (PGE2)

Enhanced platelet aggregation(thromboxane A2)

Potentiation of histamine andbradykinen (PGE2)

Renal homeostasis and vascu-lar homeostasis: renalvasodilation, diuresis, NaCl/water excretion (PGE2 andPGI2)

Vasodilation and inhibition ofplatelet aggregation(prostacyclin PGI2)

Uterine function, embryo im-plantation (PGD2)

Modulation of thromboxane-enhanced platelet aggrega-tion versus prostacyclininhibition of platelet aggre-gation (prostacyclin PGI2)

Regulation of sleep-wake cycle(GPD2) and body tempera-ture (PGE2)


events being offset by a highly statistically significantincrease in serious thrombotic cardiovascular events.’’

This precaution was born out by the recent volun-tary worldwide withdrawal of Vioxx/rofecoxib by itsmanufacturer Merck & Co, Inc, in response to theAdenomatous Polyp Prevention on VIOXX trial (AP-PROVe). The trial, which was stopped (prior topublication) in September 2004, was designed toevaluate the efficacy of VIOXX in preventing recur-rent colorectal polyps in patients with a history ofcolorectal adenomas. The APPROVe35 study did show‘‘an increased risk for confirmed cardiovascularevents, such as heart attack and stroke, beginningafter 18 months of treatment in the patients takingVioxx compared to those taking placebo. The resultsfor the first 18 months of the APPROVe study did notshow any increased risk of confirmed cardiovascularevents on Vioxx.’’

Some COX-2–specific medications have greaterantithrombotic properties than others, and hemor-rhagic and GI risk factors also appear to vary amongavailable agents.29 Kimmel31 reported that rofecoxibwas associated with higher odds of heart attackcompared with older NSAIDs, but ‘‘no evidence foran increased (heart attack) risk from celecoxib/Celebrex, again suggesting differences within theclass of COX-2 inhibitors.’’ As a precaution, physicaltherapists should monitor for cardiovascular compli-cations in patients taking COX-2-specific medicationsuntil the degree of risk is more clearly determined infuture studies.

NSAIDs AND WOUND HEALINGNSAIDs are commonly used to reduce postinjury

and postoperative pain and inflammation. By imped-ing COX-2 proinflammatory activity, NSAIDs wouldappear beneficial to resolution of tissue injury andinflammation. The overall result, however, has provento be tissue specific. NSAIDs produce no alteration inepithelial regeneration, but induce a modest delay inmuscle strain healing during the acute (substrate)phase of inflammation and delayed healing in gastriculceration.2 In a tendon-healing study, indometha-cin/Indocin showed little effect on total collagensynthesis and may have produced increased tensilestrength in healing tendon during the proliferativephase.12 Hamstring injuries treated by physical thera-pists with and without NSAID usage showed nodifference in outcome.38

Of concern to therapists is growing evidence ofNSAID impairment of bone and cartilage healing.NSAIDs potentially increase the rate of nonunion anddelay healing in those fractures that do unite.23

Glassmann et al25 investigated the effect of clinicallyrelevant NSAID doses in patients with a spinal fusionand report a 5-fold increase in the rate of nonunionin patients taking ketoralac/Toradol 30 mg every 6 to8 hours, as needed for pain. A proposed mechanism

for this bone-healing alteration is NSAID interferencewith endochondral ossification.

A consensus of multiple data suggests that NSAIDsdo produce a modest delay in healing during theacute inflammatory phase, with no long-term differ-ence in healing outcome in epithelial, tendon, orligament healing, but significant induced delay ofbone healing and increased risk of nonunion. Toprovide the best environment for acute and chronicwound healing, therapists and surgeons should at-tempt to identify and correct any factors that mayimpede success. NSAID use provides increased com-fort and reduced inflammation, which may enhancesome therapy modalities; but this must be balancedwith limited delay of soft-tissue–healing progression,particularly during the first few days of the inflamma-tory process, and possible long-term detriment tobone healing.

NSAIDS AND THROMBOPROPHYLAXIS

All nonspecific NSAIDs inhibit both COX-1 andCOX-2 to varying degrees, but by different mecha-nisms. Aspirin, uniquely, modifies both COX-1 andCOX-2 by an irreversible mechanism. The duration ofaspirin’s effect is determined by the rate ofbiosynthetic replacement of COX-1 and COX-2.13 Allother NSAIDs similarly interfere with COX-1 andCOX-2, but by a competitive, reversible mechanism,making duration of action a function of a particularagent’s individual pharmacokinetic properties. Aspi-rin’s distinctive pharmacological action on plateletsproduces greater therapeutic predictability, making itthe recommended agent for thromboprophylaxis.Evidence is mounting that concomitant use ofibuprofen and aspirin antagonizes the platelet inhibi-tion induced by aspirin. The concomitant administra-tion of Tylenol or refecoxib/Vioxx does notantagonize the antiplatelet effect of aspirin.10 Carefulassessment of patient OTC and prescription NSAIDusage will assist therapists in recognizing potentialdrug interactions that may be deleterious to patientsand complicate modality delivery. Patients should beadvised to use aspirin only, and not the COX-2selective agents or any other NSAID alone or incombination with aspirin, for thromboprophylaxis.

PHARMACOKINETICS

Clinical consideration of drug behavior and impacton the patient is divided into 4 categories: absorp-tion, distribution, metabolism, and elimination.

Absorption

NSAIDs are typically lipid-soluble weak acids andare ideally suited for rapid absorption from the acidicstomach and duodenum. In this formulation, drugs


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tend to remain nonionized and lipophilic, and morequickly cross the cell membrane lipid bilayer20 thando hydrophilic and ionized drugs, generally allowingmore rapid onset of effect. After ingestion, mostNSAIDs will exhibit an effect within 15 to 30 minutes.Fast-onset agents will tend to demonstrate a rapidoffset and, conversely, slow-onset agents characteristi-cally demonstrate slow offset.

The time interval to perceived symptom reliefvaries with the rate of enzymatic breakdown ofpreviously synthesized prostaglandins and the timerequired for the ingested drug agent to inhibitreplacement. The onset time varies widely amongagents and with respect to symptom etiology. Patientsusing rapid-onset agents, such as ibuprofen or aspi-rin, for acute pain may note relief within minutes orhours, whereas reduction of chronic arthritic painand inflammation may require a week or more.Therapists should anticipate this onset lag and advisepatients to allow sufficient time (a week or more) forsymptom relief.

Once in the bloodstream NSAIDs, except for aspi-rin, are heavily bound to plasma proteins. Thatportion of a drug which becomes attached to serumprotein (usually albumin) is termed ‘‘protein bound’’and is inactive because it is not available for cellularuptake; only the ‘‘free’’ nonprotein-bound drug frac-tion is active (bioavailable) to exert a therapeuticeffect. Extensive protein binding (ibuprofen, for ex-ample, is 99% protein bound) indicates that largerdoses will be necessary to achieve sufficient free-drugconcentration to produce a desired effect. Of clinicalimportance, 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 thebile ducts, may demonstrate increased active serum-drug fractions. Diseases associated with hypoal-buminemia, such as rheumatoid arthritis, will alsoproduce increased active serum concentrations ofnormally heavily protein-bound NSAIDs. Serum albu-min levels are routinely recorded on standard serumchemistry lab tests, allowing the therapist to antici-pate possible alteration in active-drug concentrationand clinical effect. This is particularly important withOTC NSAID usage, where patient-generated doseschedules may not take such factors into consider-ation.

Despite the high level of NSAID protein binding, atherapeutic effect is exerted by the constant dissocia-tion of the drug from its binding protein and releaseas free or active fraction within the serum. As thefree-drug fraction is metabolized, additional protein-bound drug dissociates, maintaining a constant ratioof active free agent to protein-bound agent. Increaseddrug doses further saturate albumin, so that thebound fraction eventually peaks, resulting in anincreased free active fraction. As a result, the relation-

ship of low-dose to high-dose drug effect may benonlinear. This is seen with aspirin, where a modestadditional dosage may yield a significant increase intherapeutic or toxic effect. The monitoring therapistmust recognize that dosage change may produce anonlinear response in symptom relief and dose-related adverse effects.

Because of NSAIDs’ high protein affinity they maydisplace other more weakly protein-bound drugs,unintentionally increasing their free-drug concentra-tion.28 Warfarin (Coumadin), sulfonyl-urea hypogly-cemic agents (Diabinese, Glucatrol, Micronase, etc),and methotrexate (Folex, Mexate, and Rheumatrex)are examples of drug agents encountered in physicaltherapy practice that are competitively displaced fromtheir protein-binding sites by NSAIDs.28 Dosageshould be adjusted or concurrent administration ofthese 2 drug groups avoided.

Distribution

After absorption, NSAIDs are widely distributedthroughout most body tissues. The distribution ofNSAIDs to the synovial, muscle, and bone compart-ments is a function of serum concentration; there isno specialized tissue compartment affinity. An effec-tive dose in proper regimen and duration must betaken for sufficient diffusion of the drug into connec-tive tissue compartments typically targeted within thephysical therapy patient population. This reinforcesthe necessity of patient counseling to ensure dosageschedule compliance. The therapeutic dose foribuprofen, for example, is 2400 mg per day; butpatients using ibuprofen on a self-prescribed basisoften underdose themselves and do not achievesufficient serum-drug concentration and adequatediffusion into connective tissues for therapeutic ef-fect. Additionally, NSAIDs inhibit ongoing enzymaticproduction of inflammatory substances but do notremove or facilitate absorption of existing activeprostaglandins. As a result, single-dose or short-doseregimens may provide negligible symptom relief dueto the presence of onboard prostaglandin, continuingthe pain or inflammatory effect even in the presenceof diminished synthesis of new prostaglandin.

Metabolism

How much ingested NSAID survives the digestivesystem 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 patientcompliance and capability. The liver is responsible formetabolism and bioconversion of NSAIDs. Nearly allpharmacotherapeutic agents are metabolized byhepatic cytochrome P450 isoenzymes. Drug effect,duration, and elimination will vary with the availabil-ity of these enzymes. Two or more drugs may


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 ofhemorrhage, damage to gastrointestinalmucosa

Methotrexate All Bone marrow toxicity, renal failure, andhepatic dysfunction

Antihypertensive agents: beta blockers Indomethacin and possibly others Hypertension: avoid all NSAIDs if possible

Steroids All Possible increased gastrointestinal bleedingor ulceration

Diuretics

ACE inhibitor diuretics Indomethacin and others Reduction in diuretic effect, may exacerbatecongestive 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

compete for the same P450 enzymes, potentiallyextending the drug effects due to limited isoenzymesupply, or 1 drug agent may upregulate a particularP450 enzyme, generating more rapid metabolism of asecond medication also metabolized by the sameisoenzyme. The cytochrome P450 isoenzymes used tometabolize drug agents are limited to a rather smallgroup; medication interactions are not uncommon.When the clinician observes a drug effect beinggreater or less than anticipated, P450 isoenzymeinteractions should be investigated. Standard pharma-cology reference texts list specific isoenzymes within adrug agent’s description, allowing the practitioner toinvestigate possible interactions. Table 6 lists themore common interactions of NSAIDs with othermedications.

A vexing problem for many orally administeredmedications is first-pass effect, in which the liverimmediately renders significant metabolic degrada-tion of a drug prior to target tissue delivery. First-passeffect may quickly neutralize a large percentage ofthe ingested drug. Among NSAIDs, only aspirin anddiclofenac/Voltaren undergo substantial first-pass ef-fect and show an immediate reduction in active drugquantity following hepatic passage. Patients withhepatic dysfunction will, on an equal-dose basis, showelevated serum levels of aspirin and diclofenac com-pared to other NSAIDs. In these patients, dosagesshould be decreased to compensate for the risk ofaccidental overdosage and obviate possible impact topatient therapeutic ability.

Integration of NSAID half-life data into modalityselection permits planning for maximal drug benefitand minimized adverse impact on therapy. Half-liferefers to the time required for hepatic clearance ofone-half of the drug on board. This scheme ofhepatic drug metabolism is referred to as first-orderor concentration-independent kinetics. A 100-mgdose of a drug demonstrating a 4-hour half-life willbe reduced to 50 mg in 4 hours, 25 mg in 8 hours,12.5 mg in 12 hours, and so on. NSAIDs are oftendivided into 2 groups, based on either short orrelatively long half-lives. Table 1 shows approximatehalf-lives of representative NSAIDs. Whether in single-or multiple-dose regimens, discontinuation of a medi-cation does not change the half-life of the drugremaining in the serum. When using agents especiallyprone to significant GI disturbance, dyspepsia, orpronounced central nervous system effects (eg,indomethacin/Indocin [half-life, 3 hours]), the clini-cian should consider both drug half-life and peakserum level (attained at 2 hours with Indocin) toavoid scheduling active therapy during periods ofgreatest patient compromise. All NSAIDs may causeGI discomfort (decreased by eating food prior todrug administration, which may delay therapeuticonset) and, especially in children, sedation or dizzi-ness, which will greatly decrease patient rehabilitationcapability. In the case of ibuprofen, peak serumconcentrations are observed 1 to 2 hours followingoral administration and its half-life is 2 hours.28

Clinicians may therefore wish to provide treatmentabout 1 hour after drug ingestion, particularly when


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the patient uses ibuprofen on an as-needed basis.Ibuprofen and other medications with a short half-lifealso, as noted, demonstrate more rapid offset andre-emergence of symptoms. To avoid the problem ofrapid drug offset prior to or during treatment,scheduling consideration should be given to patientsusing medications with relatively quick onset, shorthalf-life, and frequent dosing, as opposed to long-half-life, extended-dosage-interval drugs. Extendedduration of action is a goal of pharmaceutical re-search demonstrated by the development of suchNSAIDs as oxaprozin/Daypro or piroxicam/Feldene.Potential advantages in choosing these long-actingagents are greater compliance to dosage scheduleand more gradual offset of action, balanced with apossible increase in adverse effects.

A second hepatic drug metabolism scheme iszero-order or concentration-dependent kinetics. Zero-order kinetics is encountered with NSAIDs and manyother drugs in toxic overdosage scenarios, but ischaracteristic of the salicylates (aspirin anddiflunisal/Dolobid) at therapeutic drug concentra-tion, creating a particular need for patient monitor-ing. The half-life of salicylic acid, the activemetabolite of aspirin, is 2 to 3 hours in low dosage(75-325 mg, single dose orally), wherein drug me-tabolism proceeds by first-order kinetics. But it is 15to 30 hours at higher therapeutic doses, as are oftenused for anti-inflammatory effect,34 owing to limitedhepatic metabolism capability (cytochrome P450isoenzyme), which creates a dose-dependent/zero-order kinetics elimination scheme. In zero-orderkinetics, no half-life exists; rather, a given amount(mg per hour), not percentage (half-life), of the drugis metabolized per unit time. For this reason, smallincremental increases in aspirin dosage can createmarkedly disproportionate elevation of plasma levelsas the liver becomes saturated with drug. Aspirinmetabolism, half-life, and propensity to adverse effector toxicity, therefore, vary in nonlinear relationshipwith increasing dosage.

As a result, accurate monitoring of aspirin dosageis significant to both maintenance of therapeuticbenefit and timely recognition of toxic effects.Rheumatologists at times use tinnitus, a reversibleside effect of aspirin toxicity, as an indicator ofceiling therapeutic concentrations when treating ar-thritic disorders, particularly rheumatoid arthritis.The therapist should note the presence of tinnitus,along with headache, dizziness, fever, and mentalstatus changes as a marker of aspirin toxicity. Over-dose can cause the very symptoms that the patient setout to treat: headache and fever.

A related pharmacokinetic consideration is ‘‘steady-state’’ concentration. NSAIDs produce greater benefi-cial effect when taken regularly in a dose schedulerelationship that produces near constant plasma lev-

els of the drug. The timing of dosage repetition isclinically important, because NSAIDs inhibit the pro-duction of COX-1 and COX-2 products, but do notactively promote elimination of inflammation-mediating substances from the body. Proper regulardosing of NSAIDs is far more efficacious than spo-radic.4,5 When administered on a regular intermittentdosage (eg, 250 mg every 8 hours), the interdosedrug concentration will rise and fall, but the drugwill accumulate until the amount administered perunit time is equal to the amount eliminated per unittime. At steady-state, the cycle is repeated identicallyin each interval and the average plasma concentra-tion is called the steady-state concentration. Steady-state is generally considered to be achieved after 4doses, when administered at intervals equal to thedrug’s half-life. Conversation with the patient toensure drug dose schedule compliance versus as-needed or irregular use allows more flexibility intreatment scheduling and modality delivery, withdecreased associated serum-concentration-dependentdrug effect or side-effect limitations.

Understanding NSAID metabolism is also signifi-cant to antithrombotic effect. Aspirin’s ability toinhibit platelet aggregation by suppression ofthromboxane B2 occurs 30 to 60 minutes afteringestion. As previously noted, this is an irreversibleeffect and platelets will remain inactive for the 7- to10-day duration of their circulation life.13 However,this effect is measurable for only 4 to 5 days afteraspirin discontinuation because new platelets areconstantly released into the circulation.

Alteration of platelet aggregation leading to hemor-rhagic events resulting in permanent disability arenot uncommon in patients taking NSAIDs and mayinclude GI bleeding, stroke, intracranial bleeding,hemorrhagic injury to the eye, and pulmonaryevents.27 Clinically platelet disorders are evidencedmore commonly by epistaxis, bleeding gums, ec-chymosis, and petechiae,17 whereas serum proteincoagulopathies are more associated with deep bleed-ing and risk of hemarthrosis. Aspirin has little effectin terms of bruising and there is a paucity ofreported cases of hemarthrosis resulting from aspirintherapy alone.10,20 The risk of hemorrhage increaseswith patient age, especially after age 60, and inpatients taking multiple concurrent anticoagulantmedications.20 Spontaneous hemarthrosis has beenreported with aspirin used in combination withclopidogrel/Plavix, an ADP receptor antagonist alsoused to decrease thrombogenesis.24

The clinician considering vigorous regimens ordeep modalities5 must distinguish NSAID inhibitionof platelet aggregation from coagulopathies or theeffects of antithrombotic anticoagulant medicationssuch as Warfarin/Coumadin and heparin. Specific


tests for platelet function are less frequently orderedthan lab studies measuring serum-clotting proteinfunction. The prothrombin time and partialthromboplastin time are lab tests used to assess serumprotein coagulopathies, for perioperative evaluationof serum-clotting protein function, and to monitoranticoagulant dosage in postsurgical conditions,myocardial infarct, or patients with a cerebral vascularaccident. The partial thromboplastin time andprothrombin time tests do not give information as toplatelet number or aggregation function.

Platelet effectiveness is assessed both by plateletcount and aggregation activity. Normal platelet countshould be above 140 000 per ml. This measurement ispart of the routine complete blood count (CBC) labtest. Thrombocytopenia may become clinically evi-dent, by physical signs previously noted, at plateletlevels less than 40 000 to 60 000 per ml. Plateletfunction is measured by the Ivy or Duke bleeding-time tests. Clinical correlation between bleeding-testresults and aspirin or other NSAID effects may bevariable. A newer mechanized method of quantifyingplatelet aggregation function is derived in a manneranalogous to bleeding-time tests. The instrumentdraws blood from the tube and simulates in vivovascular injury, then records the time required forplatelet attachment, activation, aggregation, andbuilding of a platelet plug at the recording apertureof the instrument.19

EliminationAfter hepatic biotransformation, NSAIDs are elimi-

nated by renal excretion. This process follows thetypical elimination scheme of other lipid-solubledrugs. As with most pharmaceutical agents, NSAIDsare converted by hepatic cytochrome P450isoenzymes to hydrophilic substances that are moreeasily excreted in the urine. Alterations in urine pHcan affect the level of ionized or nonionized drugresidue and, therefore, rates of elimination.Salicylates are more rapidly cleared at alkaline pHlevels. At pH 8.0 salicylates are cleared at about 4times the rate they are at pH 6.0. The duration ofaction of NSAIDs, like other renal-excreted drugs,can be somewhat extended in the presence of acidicfoods, which favor the nonionized lipid-soluble drugcondition, and the duration of action shortened withalkaline foods that favor ionization and water solubil-ity. In a more acidic environment, the weak acidNSAIDs remain nonionized and do not remain withthe water-soluble renal filtrate, but are reabsorbedinto the systemic circulation. The rate of eliminationalso varies with urine output. Higher urine flow ratesdecrease tubular reabsorption, while decreased flowrates increase reabsorption and systemic retention ofthe drug agent. Discussion regarding patient dietaryhabits can allow enhanced therapeutic delivery andoutcomes by modifying elimination rates of pre-

scribed medications, without altering the prescriptionregimen.

ALGORITHMS OF SELECTION

The extensive variety of NSAIDs on the marketraises the question of prescribing algorithms identify-ing a ‘‘drug of choice’’ and second- or third-choiceagents. Nahlik32 states, ‘‘All currently marketedNSAIDs have been extensively studied in clinical trialsand there is little evidence to suggest that one issignificantly more effective than another for thevariety of rheumatic disorders for which they aregenerally prescribed. Based on the evidence to date,all NSAIDs, when given in equipotent doses, havecomparable efficacy. Given this equivalence, in choos-ing a particular NSAID for an individual patient,tolerability profiles remain potential ways in which itmay be possible to differentiate between differentdrugs.’’ Practitioners tend to select between similardrugs on the basis of 3 parameters: patient compli-ance, cost to patient, and patient preference. Safaviand Hayward39 observe, ‘‘. . . preferences in NSAIDprescribing were mainly determined by which drugsenhanced compliance or were used by other prescrib-ing personnel (the ’traditional choice’), with cost tothe patient being less an influence in selection.’’OTC drugs, such as aspirin, ibuprofen, and na-proxen, are first-line drugs based on cost and avail-ability.

Nevertheless, some consistent themes are found inmultiple studies using differing methodologies andsettings. Drugs with longer half-lives, such aspiroxicam, ketoprofin, and azapropazone, are associ-ated with the highest risk for adverse effect and,conversely, those agents with shorter half-lives demon-strate lower risk. Ibuprofen, for example, with ahalf-life of 2 hours, most consistently shows lower riskfor adverse GI events in standard dosage (�1500mg/d), though in higher dosage (�1500-2400 mg/d)the risk becomes comparable to other NSAIDs takenat standard dosage. A simplified method of drugagent selection is presented in Table 7.

The effect of a given NSAID will vary amongindividual patients, sometimes leading to trial ofseveral different agents in an effort to obtain the besttherapeutic effect. NSAIDs are classified by chemicalstructure, allowing products of differing chemicalfamilies to be selected as replacements for ineffectiveagents. In clinical practice, 7 to 10 days is generallylong enough (with the exception of specific long-onset agents such as piroxicam/Feldene) to ascertainthe effect of a given drug.28 Patients should beencouraged to continue taking a trial medication atleast that long before concluding ineffectiveness.Once an effective drug is identified, the dosage maybe gradually reduced to find the lowest effective dosefor the patient.


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TABLE 7. Nonsteroidal anti-inflammatory drug (NSAID) selection.

Inflammation or pain andinflammation

↓Assess risk factors for

gastrointestinal or renal toxicity↓

If no risk factors↓

Nonselective NSAID

Inflammation or pain andinflammation

↓Assess risk factors for

gastrointestinal or renal toxicity↓

If risk factors present↓

Nonselective NSAID plus gastroprotectiveagent or COX-2 selective agent;

Gastrointestinal bleedingcan still occur

Pain only↓

Acetaminophen

CONCLUSION

Designing comprehensive rehabilitation programsrequires an understanding of the pharmacologicalproperties of prescribed and OTC medications usedby patients. Due to the prevalence of both OTC andprescription NSAIDs within the physical therapy pa-tient population, these drugs play a significant role inclinical practice. An appreciation of the manner inwhich the pharmacodynamic and pharmacokineticproperties of NSAIDs affect the individual patientgenerates a broad-spectrum approach to modalityselection and delivery. Although NSAID drug agentsoffer an impressive spectrum of benefits, they also areassociated with potential side effects of implication torehabilitation success. Therapists must be cognizantof these pharmacological effects and balance the painrelief, anti-inflammatory effect, and antithromboticbenefits provided by these medications against poten-tial alterations in healing, GI disturbance, hemor-rhagic risk, renal toxicity, cardiovascular risk, andcentral nervous system effects when discussing andplanning therapy with patients. New selective COX-2drugs offer NSAID benefits with moderately reducedrenal and GI toxicity and without thrombolytic effect.Some selective COX-2 agents are known to be associ-ated with greater cardiovascular risk and this contin-ues to be investigated. Recognition of drug actions,interactions, and toxic side effects advances thetherapist’s vital role in patient monitoring, protec-tion, and care. Certainly, over the course of the nextdecade, the ever-increasing incorporation of clinicalpharmacology into physical therapy practice willprove a valuable benefit to the patient and theprogression of the physical therapy profession.

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Pharmacology in Rehabilitation_ Nonsteroidal Anti-Inflammato