NSAIDs: Where Do We Go From Here?

   Nonsteroidal antiinflammatory drugs (NSAIDs) are among the most widely used medications today. Considering their well-documented efficacy in managing fever, mild to moderate pain and, at higher doses, inflammation, such widespread use is generally appropriate. In 1997, over 74 million NSAID prescriptions were dispensed in the United States, representing approximately 4.5 percent of all prescriptions. In addition, nonprescription NSAIDs such as aspirin and ibuprofen contribute significantly to the use of this class of medications. It is estimated that 1 to 2 percent of the North American population use NSAIDs on a daily basis.

   NSAIDs have proven efficacy in a variety of disorders associated with pain and inflammation. Although Food and Drug Administration (FDA)-approved labeling differs to varying degrees for NSAIDs marketed in the United States, this does not always reflect actual differences in efficacy among these agents. (See “NSAIDs: What The FDA Is Advising” below.) By and large, selecting a NSAID for most conditions is largely empiric with exceptions in a few instances.

   For years, NSAIDs have been a mainstay in the treatment of various arthropathies including rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In regard to the NSAIDs approved for treating rheumatoid arthritis and osteoarthritis, all are considered to have comparable efficacy. As a result, considerations for selecting one agent over another are frequently based on the perceived incidence of gastric side effects, cost and frequency of administration. Recent reports have also raised concern that some NSAIDs may adversely affect chondrocyte function in patients with osteoarthritis. This potentially could accelerate joint deformity in these patients.

   Although this is yet to be confirmed, when it comes to osteoarthritis without a significant inflammatory component, one can frequently treat this with simple analgesics such as acetaminophen. When treating ankylosing spondylitis, indomethacin is considered the drug of choice based on its greater than 90 percent efficacy. However, clinicians have used other NSAIDs with good success in treating this condition.

   NSAIDs frequently are indicated for the treatment of mild to moderate pain associated with a variety of conditions, including post-extraction dental pain, episiotomy pain and pain due to soft tissue injuries. In many cases, their efficacy is comparable to many commonly used oral codeine-containing medications. NSAIDs also are used widely for the treatment of pain and inflammation associated with musculoskeletal disorders and for muscle contraction headaches. However, indomethacin is not recommended in the latter condition because of its ability to constrict cerebral vessels.

   One can effectively use NSAID therapy to treat primary dysmenorrhea, which is characterized by prostaglandin-mediated uterine contractions. Aspirin in doses of 500 mg and 600 mg is less effective than other NSAIDs in treating this condition. Also keep in mind that response rates to diclofenac may be lower than other NSAIDs due to its short half-life and sequestering in synovial fluid.

   Phenylbutazone and indomethacin have been the most widely used NSAIDs for treating gout but other NSAIDs also have demonstrated efficacy. Based on their more favorable adverse effect profiles, indomethacin and other NSAIDs are preferred over phenylbutazone. For acute attacks of gout, one would usually administer a large NSAID loading dose initially and subsequently follow the usual recommended doses.

   The safety and efficacy of most NSAIDs are not established when it comes to treating children. In regard to the marketed NSAIDs, only naproxen, naproxen sodium and tolmetin have approved labeling for juvenile rheumatoid arthritis and only naproxen is available in a liquid formulation. Indomethacin is also available as a suspension but is generally avoided in pediatric patients because of an alleged, albeit unconfirmed, relationship between its use and an increased risk of infection in children.

Understanding The Pharmacology Of NSAIDs

   Although the exact mechanism of action of NSAIDs is not completely understood, it is clear they possess potent analgesic, antiinflammatory and antipyretic effects. For years, it generally has been accepted that the major therapeutic effect of aspirin and the NSAIDs results from inhibition of prostaglandin synthesis. A large body of experimental evidence supports this theory by demonstrating a correlation between the antiinflammatory effects of NSAIDs and their in vitro potency as prostaglandin synthesis inhibitors.

   In response to trauma or other noxious stimuli, substances such as serotonin, bradykinin, histamine and prostaglandins are released from body tissues. Although prostaglandins are not direct mediators of pain, their release sensitizes afferent nociceptors to the pain-producing effects of bradykinin, histamine and possibly other substances. The effects of prostaglandins on inflammation are more complex and not completely understood. They appear to potentiate the actions of bradykinin and histamine on blood vessels, resulting in increased vascular permeability and vasodilatation of arterioles in the microcirculation.

   Prostaglandins are end products of the oxidative metabolism of arachidonic acid. Arachidonic acid is stored primarily in phospholipids of cell membranes and is liberated by phospholipases in response to tissue trauma. Cyclooxygenase and lipoxygenase enzymes catalyze the metabolism of arachidonic acid. Prostaglandins, prostacyclins and thromboxanes are produced by the cyclooxygenase pathway whereas leukotrienes and hydroperoxyeicosatetraenoic acids are produced by the lipoxygenase pathway.

   It is apparent that NSAIDs inhibit the synthesis of prostaglandins that have modulating effects on the pain and inflammation associated with the tissue injury. Although the exact contribution of nonprostaglandin effects to NSAID efficacy is unclear, they do appear to contribute to the antiinflammatory effects of NSAIDs. For years, it has been known that the dosing of aspirin and other NSAIDs necessary to suppress prostaglandin synthesis is lower than the dose necessary to produce antiinflammatory effects. This suggests the involvement of nonprostaglandin-related mechanisms. Additional evidence for this concept is based on the antiinflammatory effects of nonacetylated salicylates (i.e., sodium salicylate, choline salicylate) that have negligible inhibitory effects on prostaglandin synthesis but possess good analgesic and antiinflammatory activity.

What The Research Reveals

   As a result, recent research has focused on possible NSAID inhibitory effects on other proinflammatory mediators. Numerous in vitro studies have demonstrated a variety of nonprostaglandin antiinflammatory effects at NSAID concentrations comparable to those produced at antiinflammatory doses. These effects include: inhibiting the activation and aggregation of inflammatory cells such as neutrophils; preventing the release of lysosomal enzymes; inhibiting superoxide generation by neutrophils; and scavenging free oxygen radicals.

   Although it appears that NSAIDs do not affect the primary lipoxygenase pathway (5-lipoxygenase), some NSAIDs may inhibit other lipoxygenase pathways (i.e., 15-lipoxygenase) that have been identified but not fully characterized. The end products of lipoxygenase metabolism also are important in the inflammatory process. Some of the nonprostaglandin effects of NSAIDs vary from one agent to another based on in vitro studies but data in humans are too limited to determine if these differences are clinically important.

   Further complicating the understanding of NSAID and antiinflammatory effects is the evidence that some prostaglandins possess antiinflammatory actions under certain conditions. This paradoxical effect is not surprising given the well-documented opposing effects of different prostaglandins on other physiologic processes. It is apparent that the mechanism of action of NSAIDs is not completely understood but likely is multifaceted.

A Guide To The Pharmacokinetics Of NSAIDs

   The majority of NSAIDs are rapidly and extensively absorbed after oral administration. However, because of extensive hydrolysis by esterases in the gastrointestinal (GI) mucosa, liver and circulation, the bioavailability of unhydrolyzed aspirin is only about 65 percent. The significant first-pass liver metabolism of aspirin also contributes to this lower bioavailability. In general, NSAID peak serum concentrations occur within three hours after oral administration. The sustained release formulation of indomethacin produces a slightly delayed and prolonged plasma concentration profile compared to other NSAIDs. Sulindac, the only NSAID that is a prodrug, is converted to its active sulfide metabolite following systemic absorption.

   In general, nonsalicylate NSAIDs are lipid soluble, weakly acidic (pKa<5) and extensively bound to plasma proteins. More than 98 percent of an absorbed NSAID dose is bound to albumin and plasma proteins. The exceptions are sulindac (93.1 percent) and unhydrolyzed aspirin (33 percent). Salicylate, an active byproduct of aspirin hydrolysis, is approximately 85 to 95 percent bound to serum proteins (mainly albumin). Salicylate binding to serum albumin is decreased among elderly patients and among patients with rheumatoid arthritis. However, this does not appear to occur with ibuprofen, flurbiprofen or indomethacin. Under normal conditions, the volume of distribution of NSAIDs, including aspirin, ranges from 0.1 to 0.2 L/kg. The fraction of unbound drug and accordingly, the volume of distribution, increase slightly when albumin levels decrease due to altered physiologic states (i.e., renal failure, hypoalbuminemia, rheumatoid arthritis, hepatic disease).

   When it comes to treating patients with arthritis and other conditions associated with joint inflammation, NSAID distribution into the synovium is required for therapeutic efficacy. For patients with an inflammatory process, the total concentration of NSAIDs in the synovial fluid can range from 30 to 80 percent of the serum concentration. The lower synovial fluid concentrations are a result of the extensive protein binding that limits the amount of drug that is transferred across the synovial membrane into the synovial compartment. However, a larger proportion of unbound drug can be found in the synovial fluid than in the serum due to the lower synovial fluid protein and albumin concentrations. In addition to protein binding, other factors that can affect transport into the synovial fluid include the molecular weight of the NSAID, the acidic pH of the synovial fluid and the nature of the joint disorder.

   Patients with an active inflammatory process exhibit higher NSAID concentration in their synovial fluid than patients with no inflammation. For example, a larger synovial fluid to plasma ratio exists in patients with rheumatoid arthritis compared to those with osteoarthritis. Most NSAIDs are weak acids and the acidic pH of the synovial fluid promotes their uptake. Once an equilibrium is achieved between the serum and the synovial fluid concentrations for short half-life NSAIDs, synovial concentrations remain constant and may even exceed serum concentrations during the course of the dosing interval. Over a 12-hour dosing interval, the synovial fluid concentration actually varies less than the serum concentration. Similarly, the more rapid NSAID elimination from the serum, in comparison with the synovial fluid, indicates that trapping of the NSAID in synovial fluid may occur.

   Some investigators have suggested dosing short-acting NSAIDs every 12 hours rather than every six hours due to their relatively constant synovial fluid concentrations. However, this requires further investigation because plasma concentrations are highly variable and near zero by 12 hours after dosing. In contrast, NSAIDs with a long elimination half-life maintain more constant serum concentrations that approach equilibrium with synovial fluid concentrations, suggesting that one may use serum concentrations as a guide to clinical efficacy.

Understanding How NSAIDs Are Metabolized And How It Affects Dosing Considerations

   Most NSAIDs undergo hepatic biotransformation either through oxidation or glucuronide conjugation. As a result, patients with hepatic dysfunction or cirrhosis may require dosage alterations. Sulindac, a prodrug that requires conversion to its active sulfide moiety, can be reconverted systemically back to its parent compound.
   Similarly, since indomethacin and sulindac are also metabolized and excreted through the biliary tract, they can accumulate in patients with biliary obstruction. In one study, a three-fold increase in the area under the concentration time curve for sulindac and a four-fold increase for its sulfide metabolite occurred in patients with alcoholic liver disease.

   Therefore, one may need to decrease sunlindac doses to one-fourth of the normal dose in patients with hepatic disease. Since aspirin, ibuprofen, indomethacin, piroxicam and phenylbutazone are metabolized by multiple pathways, dosage adjustments are not usually necessary in patients with hepatic disease or in elderly patients with normal renal function. Patients who have hypoalbuminemia due to liver disease or renal failure have an increased free fraction of the drug in serum, which is ultimately available for distribution into tissue sites or for renal excretion.

What You Should Know About The Half-Lives Of NSAIDs

   NSAIDs generally can be categorized on the basis of their plasma elimination half-lives. Since steady state serum concentrations are not achieved for three to five half-lives, maximum clinical effects are not as evident soon after initiating therapy with long half-life NSAIDs as they are after short half-life NSAIDs. Since all NSAIDs have similar volumes of distribution, differences in half-lives are due to differences in clearance.

   Although less than 10 percent of a NSAID dose is excreted in an unmetabolized form by the kidneys, renal impairment can lead to accumulation of the parent drug and its metabolites. However, renal impairment does not interfere with the hepatic metabolism of NSAIDs. NSAIDs that metabolize to form acyl glucuronide conjugates (i.e., ketoprofen, fenoprofen, naproxen, diflunisal) can accumulate in elderly patients and in those with renal failure. The conjugated metabolites can be deconjugated back to the parent drug, which is recirculated and reabsorbed. Similarly, these compounds can be excreted into the biliary tract and undergo enterohepatic recycling.

   Since accumulation of these NSAIDs could potentially result in an increased risk for adverse effects of drug interactions, appropriate dosage adjustments are required. One should decrease naproxen and ketoprofen doses in patients with renal failure whereas doses of ibuprofen, etodolac, piroxicam, diclofenac, and diflusinal do not require dosage adjustments. Since NSAIDs are not removed during hemodialysis, dosage adjustments are not necessary among patients undergoing dialysis.

Gauging Patient Response To NSAID Therapy

   It is generally accepted that patient responsiveness to and preference for individual NSAIDs vary significantly. It is not clear whether this variability is due to clinically important pharmacodynamic differences among agents, inherent inter-patient differences or both. Numerous comparative studies in arthritis patients have demonstrated similar overall therapeutic responses for different NSAIDs when they were given comparable antiinflammatory dosages. However, marked variability in individual patient response to different NSAIDs is not uncommon.

   Several factors have been identified that can influence inter-patient variability in NSAID response and preference. In some cases, patient preference may actually represent greater tolerability (i.e., less frequent GI complaints) rather than superior efficacy. Additionally, when clinicians employ NSAIDs to help treat chronic conditions such as rheumatoid arthritis, periodic changes in disease severity may account for changes in perceived efficacy. In some cases, differences in patient response may represent true pharmacodynamic differences between NSAIDs. These differences could result from differences in the nonprostaglandin-medicated actions of these drugs. Although researchers have shown variable effects on nonprostaglandin pathways in vitro for several NSAIDs, the clinical significance of these effects is unknown. As a result, the current understanding of inter-patient variability suggests that patient-related and drug-related factors may both play important roles.

   Whenever prescribing NSAID therapy, it is important for clinicians to ensure the course of therapy allows for adequate assessment of NSAID efficacy. For short half-life agents, one may see maximum effects within only a few days of initiation of therapy whereas a two- to three-week course is necessary to judge the efficacy of long half-life agents such as piroxicam. When patients do not respond to an adequate course of therapy with a NSAID, using another drug from a different chemical class is frequently recommended.

   As a result of the pronounced pharmacologic effects of NSAIDs on multiple organ systems, adverse effects are inevitable. Out of all adverse drug reactions reported in the U.S. and the United Kingdom through spontaneous reporting systems, approximately 20 to 25 percent are related to NSAID-induced inhibition of prostaglandin synthesis whereas other adverse drug reaction reports appear to be unique to individuals or a limited number of NSAIDs. The most serious toxicities of NSAIDs occur in the GI tract, kidneys, hematopoietic system and the liver.

In Conclusion

   The nonsteroidal antiinflammatory drugs (NSAIDs) are a group of chemically dissimilar agents that differ in their antipyretic, analgesic and antiinflammatory activities. Aspirin is the prototype of this group. However, about 15 percent of patients show intolerance to aspirin. Therefore, these individuals may benefit from other NSAIDs. In addition, some newer NSAIDs are marginally superior to aspirin in certain patients because they have greater antiinflammatory activity, may cause less gastric irritation or can be taken less frequently. However, the newer NSAIDs are considerably more expensive than aspirin and some have proven to be more toxic in other ways. Know your patients and be aware of potential complications.

Dr. Iorio is Chairman and Associate Professor in the Department of Medical Sciences at the New York College of Podiatric Medicine. He is a Fellow of the American College of Foot and Ankle Surgeons.

References:

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