nsaids

Phys Med Rehabil Clin N Am

17 (2006) 347–354

Nonsteroidal Anti-Inflammatory Drugs

Carin E. Dugowson, MD, MPH*,Priya Gnanashanmugam, MD

Division of Rheumatology, University of Washington, Box 356428, Seattle,

WA 98195-3414, USA

In Case 4, a 34-year-old male roofer fell off a roof 1 year ago and sus-tained an L1 vertebral body fracture. There was no neurologic compromise.An orthopedist recommended against surgical management. The patientwas treated conservatively with bracing for several weeks and went throughextensive physical therapy with only modest benefit. Radiographically, hiscondition stabilized, with no identifiable abnormality other than a 30%loss of height of the L1 vertebral body. He has undergone evaluation byan interventional pain physician. Diagnostic injections including medialbranch blocks and discography at the thoracolumbar junction did not delin-eate any specific pain generator that might be a target for interventionaltherapy. The patient reports severe pain at the thoracolumbar junction.He has no symptoms in his lower extremities.

A patient like this one is almost certain to have undergone one or moretrials of nonsteroidal anti-inflammatory drugs (NSAIDs). As a group, thesemedications are the most widely used medications in the world. Many areavailable over the counter. Although many of their adverse effects arewell recognized, recent studies have identified new concerns. It is importantto balance the benefits with the potential adverse effects of these drugs andto tailor therapy to the individual patient.

History

Derived from willow bark, salicin was used by MacIagan in 1874 to treatinflammation in rheumatic fever. Later, a more efficacious and better toler-ated synthetic derivative, aspirin, was produced by Felix Hoffman of theBayer company [1]. In 1963, indomethacin was introduced to treat

* Corresponding author.

E-mail address: [email protected] (C.E. Dugowson).

1047-9651/06/$ - see front matter � 2006 Elsevier Inc. All rights reserved.

doi:10.1016/j.pmr.2005.12.012 pmr.theclinics.com

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348 DUGOWSON & GNANASHANMUGAM

rheumatoid arthritis, and this was followed by the development of manyother anti-inflammatory agents. The poor gastrointestinal (GI) tolerabilityof this class of drugs, coupled with their widespread use, led to the develop-ment of selective agents known as COX-2 inhibitors.

Mechanism of action

The mechanism of action of NSAIDs can be divided into their effects oninflammation, pain, and fever [1].

Anti-inflammatory effect

NSAIDs exert their anti-inflammatory effect through inhibition of pros-taglandin G/H synthase, or cyclooxygenase, which is the enzyme catalyzingthe transformation of arachidonic acid to prostaglandins and thromboxanes[1]. This enzyme has two recognized forms: cox-1 and cox-2. Selective inhi-bition of cox-2 leads to decreased GI side effects. Recent work suggests thatactivation of endothelial cells and expression of cell adhesion molecules playa role in targeting circulating cells to inflammatory sites. NSAIDs may in-hibit expression of these cell adhesion molecules and may directly inhibit ac-tivation and function of neutrophils.

Analgesic effect

Although they are classified as mild analgesics, NSAIDs have a more sig-nificant effect on pain resulting from the increased peripheral sensitizationthat occurs during inflammation and leads nociceptors to respond to stimulithat are normally painless. In particular, it is believed that inflammationleads to a lowering of the response threshold of polymodal nociceptors [3].

Antipyretic effect

NSAIDs exert their antipyretic effect by inhibition of prostaglandin E2(PGE2) synthesis, which is responsible for triggering the hypothalamus toincrease body temperature during inflammation [3].

Pharmacokinetics

NSAIDS are metabolized primarily in the liver [1]. They vary in theirhalf-lives and bioavailability. Given the multitude of available NSAIDs,the variability of their half-lives allows for different dosing regimens. Al-though decreased frequency of dosing improves compliance as a generalrule, consideration must be given to the increase in renal dysfunction asso-ciated with longer-acting NSAIDs. It has also been speculated that use ofdaily dosed medications, by improving compliance, may increase the risk

349NONSTEROIDAL ANTI-INFLAMMATORY DRUGS

for GI bleeding. Variability in susceptibility to adverse effects of variousNSAIDs does not seem to be due to difference in pharmacokinetics. Hepaticfunction, renal function, and age must be considered before prescribing anddosing.

Clinical uses

NSAIDs are classified as mild analgesics [4]. Although this designationsays something about the potency of NSAIDs, it is misleading withoutthe qualification that a major reason for the analgesic effect of NSAIDs isthat they inhibit inflammation. Thus, pain mediated by inflammation ismuch more likely to be relieved by NSAIDs than pain that is unrelated toinflammation. Examples of the former include a variety of rheumatologicconditions, such as ankylosing spondylitis and rheumatoid arthritis. Osteo-arthritis involves at least intermittent inflammation and can also respond toNSAIDs. Most importantly, local inflammation routinely occurs in re-sponse to acute injury of virtually any structure in the body [5]. Thus,NSAIDs are a logical choice for acute pain management after injury [6].NSAIDs are widely used in the treatment of acute musculoskeletal injuries,and there is evidence for their ability to provide symptomatic relief of con-ditions such as acute low back pain [7,8].

NSAIDs are also commonly used in chronic musculoskeletal pain, al-though the rationale for their use in that setting is less clear because the de-gree to which inflammation plays a role in chronic musculoskeletal pain isnot known. The literature on the efficacy of NSAIDs in chronic musculo-skeletal pain is mixed. There is convincing evidence that NSAIDs are inef-fective in treating fibromyalgia [9]. In contrast, there is evidence tosupport the use of NSAIDs in chronic spinal pain like that described inCase 4. However, this evidence comes from trials lasting no more thana few weeks [10–12], and other studies question the effectiveness of NSAIDsin spinal disorders [13].

Studies using large numbers of patients do not show a benefit of one typeof NSAID over another, and their proven efficacy has not been shown to besuperior to other agents, such as acetaminophen, narcotic analgesics, andmuscle relaxants [2]. Variability in therapeutic response and susceptibilityto toxicity is well recognized but poorly understood. Neither pharmacoki-netics nor serum concentrations predict either of these outcomes. It is spec-ulated that alteration of nonprostaglandin-mediated events may beimportant.

Adverse effects

In discussing adverse effects of anti-inflammatory medications, it is help-ful to distinguish among aspirin, nonselective NSAIDs, and the newer


selective cox-2 inhibitors. Although these three classes of drugs for the mostpart produce qualitatively similar adverse effects, they differ quantitativelyin the risks that they pose.

Aspirin-induced asthma

NSAIDs should be avoided in patients who have established sensitivity toaspirin. All patients who are new to NSAIDs should be warned about thisside effect. It is seen more commonly in patients who have asthma, nasalpolyps, and history of rhinitis. The prevalence of aspirin-exacerbated respi-ratory tract disease is about 10% in the general population and about 21%in adults when determined by oral provocation testing. It is associated withrhinosinusitis and nasal polyps and presents most often as rhinitis andasthma. Although patients are described as having aspirin sensitivity or as-pirin-induced asthma, they are at risk for adverse reactions from anyNSAID that inhibits cox-1 [14,15]. There is recent evidence that suggeststhat selective cox-2 inhibitors are a safe alternative in this population, butthis remains to be confirmed in large, well-controlled trials [16].

Aspirin should be used with caution in patients who have renal dysfunc-tion or bleeding disorders and in elderly patients, in whom even baby aspirincan induce common side effects. Additionally, in elderly patients, tinnitus iscommonly seen as therapeutic levels are reached. In practice, aspirin is un-commonly used for the management of musculoskeletal pain because theneed for frequent dosing, the antiplatelet effect, and the risk of GI bleeding,and other issues make for a narrow therapeutic margin.

Effects on platelets

Aspirin and nonselective NSAIDs produce inhibition of platelet functionvia their inhibition of COX1. In the case of aspirin, the inhibition is irrevers-ible, so the effect on platelet function continues for the life of the affectedplatelet (7–10 days). In contrast, nonselective NSAIDs cause a reversible in-hibition of COX1, so that the effect on platelet function corresponds to thehalf-life of the specific drug, usually lasting from 2 to 12 hours [17]. BecauseCOX-2 inhibitors have little effect on COX-1, they are less likely thannonselective NSAIDs to produce clinically significant effects on plateletfunction.

Gastrointestinal toxicity

Upper GI tract injury is a major side effect of NSAIDs and includes ab-dominal pain, dyspepsia, and gastroduodenal ulcers. Intolerance of GI sideeffects leads to withdrawal rates of about 10%. Also, nonselective NSAIDusers are four to eight times more likely to develop gastroduodenal ulcersduring therapy. Although NSAID-induced ulcer complications are de-creased with concomitant use of full-dose misoprostol, the usefulness of


the latter drug is limited by the diarrhea it causes and by the need for mul-tiple daily dosing [18]. Additionally, there is poor correlation between dys-peptic symptoms and the presence of ulcerations or erosions in thestomach or duodenum. Thus, symptoms may not be used as a guide regard-ing the risk of GI complications. A meta-analysis [19] of randomized con-trolled trials of comparing cox-2 inhibitors and nonselective NSAIDsshowed that the cox-2 inhibitors were associated with a lower incidence ofGI symptoms and symptomatic ulcers, but the studies did not providedata about the incidence of endoscopic ulcers.

In the CLASS study [20], fewer ulcers and ulcer complications were seenin the celecoxib group compared with ibuprofen or diclofenac in the initial 6months. The effect was lost, but there is uncertainty about the cause. In par-ticular, the use of low-dose aspirin in 20% of subjects and higher doses ofcelecoxib than used clinically complicate the analyses. There is also evidencethat these agents do not decrease the risk of ulcers with complications in pa-tients already at high risk for GI ulcers [21]. Also, of the COX-2 inhibitors,only rofecoxib was clearly shown to reduce the incidence of clinically signif-icant GI bleeds and other ulcer complications. This has raised questions asto whether these drugs mask the presence of ulcers by decreasing dyspepticsymptoms [19].

Some studies suggest that double-dose H2-receptor blockers and protonpump inhibitors decrease the likelihood of gastroduodenal ulcers with long-term NSAID use, but this has not been borne out in randomized controlledtrials; nor has there been clear evidence that one strategy is more effectivethan the other [22]. The preferred method of most physicians to avoid ulcerdevelopment is concomitant therapy with daily proton pump inhibitor orprescribing a selective COX-2 inhibitor.

GI side effects are more likely in elderly patients, patients who have a his-tory of GI disease, patients who have concurrent Helicobacter pylori infec-tion, patients using steroids or anticoagulants, and patients on higher dosesof NSAIDs. The risk of GI ulcer is equal to that of nonselective NSAIDs inpatients on cox-2 inhibitors who are also on aspirin [22]. GI bleeding in pa-tients on warfarin is not less in patients using COX-2 drugs than nonselec-tive NSAIDs [23].

Acute renal failure, nephrotic syndrome, and electrolyte complications

Due to constitutive expression of COX-2 in the kidneys, the effects ofnonselective and COX-2 selective NSAIDs on renal function, electrolyte im-balance, and peripheral edema are similar [24]. There is an increase in renaltoxicity when these agents are combined with antihypertensive agents andother potentially nephrotoxic drugs. There is a risk of peripheral edemaand hyperkalemia, particularly in patients who have diabetes, elderly pa-tients, and patients on other hyperkalemia-inducing agents such as potas-sium-sparing diuretics or angiotensin-converting enzyme (ACE) inhibitors.


Hypertension

In double-blind, randomized, controlled studies examining the effect ofcox-2 inhibitors on blood pressure, the results are conflicting. Although ro-fecoxib seems to elevate blood pressure and interfere with antihypertensiveeffects of ACE inhibitors and beta blockers, the effect of celecoxib varieswith the study design. Patients at particular risk of hypertension from theuse of COX-2 inhibitors include those who have congestive heart failure,liver disease, and kidney disease and those taking ACE inhibitors or di-uretics [25].

Cardiovascular effects

The selective COX-2 inhibitors do not inhibit platelet thromboxane A2,which is derived from COX-1. Animal studies show that the prostacyclinsuppression mediated by COX-2 enhances responses to agonists that arethrombogenic and that increase blood pressure and atherosclerosis. As a re-sult of these and other effects, COX-2 inhibitors, in comparison with nonse-lective NSAIDs, alter the balance antithrombotic and prothromboticpathways in a way that promotes thrombogenesis [26]. This is the scientificbasis behind the emerging evidence of risk of cardiovascular events with useof COX-2 inhibitors.

Cardiovascular toxicity was seen clinically in studies demonstratingthat the use of rofecoxib (VIGOR) and valdecoxib (two studies of its use inpost-CABG patients) led to an increase in atherosclerotic events and thewithdrawal of rofecoxib from the market. The FDA’s verdict regardingthe cardiovascular hazard of the COX-2 inhibitors as a group remains tobe seen. The evidence suggests that these drugs as a class increase the likeli-hood of a cardiovascular event, particularly in patients who are at increasedrisk. Many physicians have elected not to prescribe COX-2 inhibitors to pa-tients who have a history of myocardial infarction or ischemic stroke. Con-sultation with a cardiologist is often appropriate for risk assessment andmanagement of cardiovascular issues.

Addendum: case histories

Case 1

A 19-year-old man was involved in an accident while driving a motorcy-cle. He was not wearing a helmet. He hit his head into a telephone pole dur-ing the accident and sustained a skull fracture with intracerebral bleed. Hewas comatose for 10 days. He did not sustain any other significant injuries inthe accident. After his coma resolved, he demonstrated significant cognitivedifficulties, along with right-sided paresis and spasticity. He reports diffusepain in his right lower extremity. There is no obvious orthopedic reasonfor this. His right lower extremity pain is thought to be a neuropathic


type of pain secondary to his brain injury, with some aggravation caused byhis spasticity.

Case 2

A 70-year-old woman has been treated for diabetes mellitus for the past10 years. She complains of burning pain in both feet. The pain is severeenough that she reports substantial limitations in her physical activitiesand severe disruption of her sleep. She has undergone electrodiagnostic test-ing, which demonstrated abnormalities consistent with a diabetic polyneur-opathy. The patient’s general medical status is noteworthy in that she hada mild myocardial infarction 3 years ago, with subsequent angioplasty. Fol-low-up evaluations have shown normal left ventricular function and mild tomoderate coronary artery stenosis. The patient has a history of hypertensionadequately controlled with Lisinopril.

In cases of neuropathic pain (Cases 1 and 2), there is no clear long-termbenefit of NSAIDs [27]. There may be a role in breakthrough pain whenother long-term agents are in place. Combined use of NSAIDs with narcoticanalgesics is thought to improve pain relief and to reduce opioid use [28].Thus, in Case 1, NSAID use may decrease the patient’s long-term needfor opioids and may be a useful adjunctive therapy provided the bleedingfrom the acute traumatic episode is controlled. The decision to use anNSAID and the dose must be weighed against the individual patient’s riskprofile. In Case 2, the elderly hypertensive patient with coronary artery dis-ease is on an ACE inhibitor, and aspirin use could put the patient at in-creased risk for adverse effects from NSAID use. Case 3 describes a painsyndrome (fibromyalgia) for which NSAIDs have been shown to be ineffec-tive. NSAIDs are a commonly used and effective group of medications formany pain situations. However, the increased awareness of complicationsassociated with their use mandates our increased caution when prescribingthese drugs.

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