Upon completion, the pharmacist should be able to:

1. Define the class of nonsteroidal anti-inflammatory drugs (NSAIDs) as regards their principles of pharmacologic and therapeutic actions;
2. Differentiate between thromboembolic outcomes that follow inhibition of cyclooxygenase 1 and 2 (COX-1 and COX-2) enzymes with NSAIDs;
3. Differentiate between OTC analgesics with respect to their efficacy in treatment of osteoarthritis pain and symptoms;
4. Describe new labeling for OTC NSAIDs;
5. List key clinical observations from recent clinical trials that replaced safety concern with safety assurance for OTC NSAIDs;
6. Define the pharmacist’s role in patient counseling on use of OTC NSAIDs in osteoarthritis pain; and
7. Select specific, clinically relevant information to support professional advice when counseling on the use of OTC NSAIDs.

Reports suggesting there may be a link between certain nonsteroidal anti-inflammatory drugs (NSAIDs) and adverse cardiovascular events raise questions about what to recommend to patients with osteoarthritis pain. The issue is confounded by published results of clinical trials that implicate certain NSAIDs, while other trials seem to contradict the implications. Such concern has been the case with ibuprofen and naproxen, NSAIDs available for use without a prescription. Both drugs are approved for self-treatment of painful osteoarthritis of mild to moderate intensity and are effective for this purpose. Both have also been demonstrated in numerous controlled clinical trials to be safe when used according to their manufacturers’ directions. Added to this concern about safety is further confusion because of recent reports that another widely used NSAID for self-treatment of osteoarthritis, acetaminophen, may share some of the same problems to compromise safety that are alleged for the NSAIDs.

This monograph will discuss the basic and clinical sciences that underlie the current situation regarding a potential implication that nonprescription NSAIDs put their users at higher risk for adverse thromboembolic events. It will also comment on the drugs’ use in general as analgesics in osteoarthritis. It will clarify the place of acetaminophen in NSAID therapeutics. Finally, it will present commentary relative to the selection of appropriate nonprescription analgesic drugs and provide helpful information to pass along to patients with osteoarthritis and their family members when appropriate, to maximize the drugs’ safety and efficacy in osteoarthritic pain.

OSTEOARTHRITIS

Arthritis affects nearly 66 million Americans, or about one in three adults.1 The most common of the arthritides, osteoarthritis,² correlates positively with advancing age although it can afflict younger people as well. A survey of women under 45 years of age revealed 2% incidence of radiographic evidence of osteoarthritis, increasing to 30% between ages 45 and 64 years, and to 68% for those older than 65 years.³ The number of persons in the United States aged 65 years or older projected to have arthritis or chronic joint symptoms is expected to swell to more than 41 million by 2030.⁴ Compounding the growing problem is the enormous economic obligation for treating arthritis, its complications, and resulting disability. Arthritis costs the nation’s economy more than $86 billion annually.^5,6 Of this total, $51.1 billion are direct medical-related costs, and $35.1 billion are indirect costs or lost wages.6 Osteoarthritis represents failure of the diarthrodial (movable, synovial-lined) joint. Primary (idiopathic) osteoarthritis is the most common form of the disease and no predisposing condition is known. Secondary osteoarthritis differs from the primary form in that there is an underlying cause.³ Risk factors that correlate with osteoarthritis are summarized in Table 1.

Table 1. Risk Factors for Osteoarthritis³

• Age
• Female gender
• Race
• Genetic factors
• Major joint trauma^*
• Repetitive stress, eg, vocational^*
• Obesity^*
• Congenital/developmental defects^*
• Prior inflammatory joint disease
• Metabolic/endocrine disorders

_____________
^*Potentially modifiable.

Pain is the paramount symptom of osteoarthritis. Pain of osteoarthritis may arise from periosteal elevation, trabecular microfractures, capsular distension, and/or synovial inflammation.⁷ It is characterized as a deep, aching sensation that intensifies with motion and improves at rest. It is usually intermittent and often mild, but can become persistent and severe.⁸ Stiffness is common especially in the early morning or following periods of inactivity and is short-lived, usually 20 minutes or less. Inflammation may be mild and limited to the affected joint(s); patients with osteoarthritic joint pain may not show radiographic evidence of disease early on, but the inflammatory process is nevertheless underway.⁹ Inflammation is now believed to contribute to osteoarthritic pain more than previously thought,¹⁰ therefore, effective management of osteoarthritic pain infers the use of drugs that block the inflammatory process.

INFLAMMATION AND PAIN
Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage.¹¹ It may be acute or persistent (ie, chronic), nociceptive or neuropathic. Nociceptive pain results from mechanical, chemical, or thermal irritation of peripheral sensory nerves following trauma, or occurring in association with degenerative and/or inflammatory processes such as osteoarthritis. Nociceptive pain is sharp and well localized. Neuropathic pain is less well localized and brought on by damage to peripheral or central neurons, such as with postherpetic neuralgia and diabetic neuropathy. Pain that persists 3 or more months beyond the time when an acute injury would be expected to heal can lead to complex patient presentations, often with conflicting psychological features. These include complaints of non-restorative sleep, lethargy, depression, poor concentration, and impaired ambulation. This pain is often designated chronic, a term associated with negative connotations. In its place, the descriptors persistent or long-lasting have been suggested.¹² The World Health Organization reports that persons with persistent pain are four times more likely than those without pain to suffer from depression or anxiety, and twice as likely to experience difficulty working.¹³

Since pain can have an overwhelmingly negative influence on nearly every aspect of life, sufferers are willing to undertake whatever is necessary to relieve it. In fact, pain may become the primary focus of a person’s existence, overshadowing nearly everything else until suitable relief has been achieved. As such, pain can be detrimental to quality of life by greatly limiting a person’s capacity to function normally in daily responsibilities involving family, social, and vocational roles. Understandably, this can also influence family members and caregivers adversely.^14,15 Pain does not need to be excessively severe to significantly reduce quality of life since even mild or moderate pain, especially if unrelenting, may have a negative impact on a person’s physical and emotional status.^14,16 Such negative impact on quality of life is universal, spanning every age and stage of life, and has been demonstrated for nearly every form of pain, including persistent nonmalignant pain such as that associated with osteoarthritis.¹⁴

Pathogenesis
Relevant to the pathogenesis of inflammatory pain is an understanding of the biologic actions of prostaglandins, including their mechanisms of synthesis and inhibition. Prostaglandins are fatty acid derivatives that are described as autacoids. Autacoids are short-range hormones that are formed rapidly, exert their effects locally, then either decay spontaneously or are destroyed enzymatically.¹⁷ Prostaglandins have an active role in a variety of physiologic and pathologic processes, including inflammation and pain.

Prostaglandins in osteoarthritis.—Prostaglandins are synthesized from arachidonic acid, a 20-carbon polyunsaturated fatty acid (Figure 1). Arachidonic acid is supplied from dietary sources or derived by conversion from linoleic acid. It is a normal component of cellular membrane phospholipids and released through hydrolysis by cellular phospholipases by mechanical and physical stimuli, or other chemical mediators.18 Arachidonic acid metabolites, called eicosanoids, are synthesized by catalytic activity of cyclooxygenase (prostaglandins and thromboxanes) and lipoxygenase (leukotrienes) enzymes. It is now accepted that a mixture of leukotrienes constitutes the substance formerly known as the “slow-reacting substance of anaphylaxis” (SRS-A). Eicosanoids can mediate virtually every step of inflammation.

Figure 1. Mechanism of action of NSAIDs.

Present in high concentrations in inflammatory fluids, prostaglandins are potent mediators of inflammation. They do not cause pain on their own; rather, they are believed to sensitize nerve endings (ie, pain receptors) to mechanical and chemical stimulation.^17,19 Prostaglandin E₂ (PGE₂) and prostaglandin I₂ (PGI₂) are particularly potent pain inducers. Other prostaglandins may contribute to pain by their interaction with additional chemical mediators. For example, prostaglandin E₁ (PGE₁) incites pain only when bradykinin or histamine is also present. Intervention with pharmacologic agents that inhibit the actions of prostaglandins, as described subsequently, reduces the severity of inflammation and consequently pain.¹⁷

Cyclooxygenase.—Cyclooxygenase (prostaglandin endoperoxide synthase; COX) plays a key role in several physiological functions including the process of inflammation. Two isoforms of COX, dubbed COX-1 and COX-2, have been identified to date.18 Both serve different physiologic functions. COX-1 is present in most normal cells throughout the body and is synthesized constitutively (continuously). COX-1 controls cellular integrity in that it stimulates synthesis of prostaglandins that regulate normal cellular activity, most notably platelet aggregation and homeostasis of the vasculature; and the gastrointestinal mucosa and renal system. It may therefore be considered to be a “housekeeping” enzyme.

In contrast, COX-2 is found less abundantly in many tissues. COX-2 is expressed (induced) rapidly and far more selectively than COX-1 in response to a number of local inflammatory stimuli and released in tissues as a result of damage where it initiates the characteristic response of inflammation and pain.^17,20 COX-2 appears to be constitutive in some tissues, including the brain, reproductive organs, kidney, and placenta during late gestation.¹⁸ The two isoforms differ by a single amino acid at position 509 of cyclooxygenase (COX-1, valine; COX-2, isoleucine).

Controlling Pain With NSAIDs
The major mechanism of action of NSAIDs is through inhibition of COX (Figure 2), the enzyme responsible for synthesis of prostaglandins from precursor arachidonic acid.^21,22 The non-aspirin NSAIDs differ from aspirin in that aspirin covalently modifies both COX-1 and COX-2, resulting in an irreversible inhibition of enzymatic activity. The vast majority of traditional NSAIDs, including ibuprofen and naproxen, are organic acids and act as reversible, competitive inhibitors of COX. Since inhibition is reversible, the duration of action of the traditional, nonselective NSAIDs is governed primarily by their pharmacokinetic clearance.21 As noted earlier, COX is dispersed throughout the body and involved in a wide variety of physiologic processes.

Figure 2. Differences in symptom intensity from baseline for 7 pain assessments following treatment with naproxen sodium, acetaminophen, or placebo.⁶

Discovery and characterization of COX-2 led to development of highly selective, specific COX-2 inhibitors (eg, celecoxib, rofecoxib, valdecoxib; “coxibs”). All traditional NSAIDs are nonselective in that at therapeutic concentrations, they inhibit both COX-1 and COX-2 isoforms to similar extent, although different NSAIDs inhibit COX-2 to various extent from one another. The theoretical advantage of selective COX-2 inhibition is based on their preferential inhibition of COX-2 (see Figure 2) while preserving COX-1. In theory, this provides anti-inflammatory and analgesic effects while avoiding complicating gastrointestinal (GI) toxicity and platelet inhibition associated with COX-1 inhibition.18 In reality however, the COX-2 selective inhibitors are associated with adverse GI and thromboembolic events.

ROLE OF COX-1 AND COX-2 IN THROMBOEMBOLIC EVENTS

Thromboxane A₂ (TXA₂) and prostaglandin I₂ (PGI₂; prostacyclin) are platelet-derived prostaglandins that play key roles in maintenance of vascular homeostasis. TXA₂ is prothrombotic, ie, it promotes vasoconstriction, platelet aggregation, and vascular smooth muscle proliferation. PGI₂ is antithrombotic, ie, it opposes the action of TXA₂ and produces vasodilatation and inhibition of platelet aggregation. TXA₂ synthesis is COX-1 dependent. PGI₂ synthesis is COX-2 dependent.^20,21 Clinical investigation in healthy subjects demonstrates that treatment with coxibs decreases systemic PGI₂ production without affecting TXA₂ synthesis significantly.²³ In contrast, the classical NSAIDs decrease both PGI₂ production and TXA₂ synthesis to maintain their critical balance in vasculature homeostasis. There is concern that coxibs may increase the risk for adverse cardiovascular events due to their selective inhibition of PGI₂ synthesis, which in turn would be expected to lead to vasoconstriction, increased platelet aggregation, and smooth muscle cell proliferation because of an unopposed effect of TXA₂.^18,24

MANAGEMENT OF MILD TO MODERATE PAIN OF OSTEOARTHRITIS

At present, there are no disease-modifying agents that reverse osteoarthritis.²⁵ The first and most important treatment goal, therefore, is to decrease the severity and duration of pain. An initial message to encourage patients with osteoarthritis is that, while their disease is not curable at present, pain can be effectively controlled in almost all patients.²⁶ This will help achieve the second goal of therapy, which is to minimize suffering, functional limitation, and eventual disability. Additional goals include preventing acute pain from becoming persistent and unrelenting, thus optimizing quality of life.16 Preferred initial treatment includes nonpharmacologic therapies such as aerobic exercise, muscle strengthening, adjustment of life activities, education, support devices, and weight loss if overweight.^27-29 If these measures fail to bring relief, pharmacologic therapy can be added. Generally, patients who do not meet the criteria for exclusion from self-care (Table 2) can self-treat their pain. Used as directed, nonprescription analgesics are safe and effective for treatment of mild to moderate pain of osteoarthritis.³⁰

Table 2. Exclusions to Self-Treatment of Osteoarthritis and Other Musculoskeletal Pain^*36 

• Pain persisting longer than 2 weeks
• Pain with nausea or severe vomiting
• Weakness in any limb
• Pain in a red, hot, or swollen joint (with or without fever)
• Suspected fracture
• Pelvic or abdominal pain (other than dysmenorrhea)
• Suspected pregnancy (last menstrual period >6 weeks ago)
• Increased intensity of pain or any change in the character of pain

Nonprescription Versus Prescription Drug Use
Some analgesics are available in both nonprescription and prescription forms, and the distinction between the two classes may be confusing to patients. To remain within the legal definition of OTC use, each agent has an approved maximum dose and duration of therapy. Confusion may be compounded when individuals who have a professionally-diagnosed pathology that requires medical supervision are advised to take an OTC analgesic listed in Table 3 for extended periods. For these persons, instructions for dosage and duration of therapy are provided by the physician rather than by directions on the products’ labels.

It should also be pointed out that there is a huge difference in the likelihood of an adverse drug reaction or drug interaction occurring in the case of a patient who has a minor ache or pain and takes a maximum OTC analgesic dose of ibuprofen 1200 mg/day for 1 week for example, versus that of a person with osteoarthritis who takes a prescription anti-inflammatory dose of 2400 to 3200 mg/day of the same drug over many months, regardless of whether ibuprofen was purchased with or without a prescription. This can greatly confound patients’ and pharmacists’ understanding of drug safety issues. For example, much of the professional data published on NSAID safety reflect actions that can be expected from doses that are clearly in the realm of prescription drug use rather than at levels representative of self-treatment criteria and, therefore, do not directly apply to OTC product uses. Realistically though, it must be emphasized that some patients will choose to self-administer OTC NSAIDs at dosages and for durations that exceed the guidelines listed in their labeling. Long-term safety studies that employ conditions in the prescription domain therefore cannot be ignored totally.

Nonprescription NSAIDs
All FDA-approved nonprescription (ie, OTC) analgesics for internal use are NSAIDs. They are sub-classed into three groups: salicylates, propionic acid derivatives (NSAIDs), and para-aminophenols. Salicylates include aspirin (acetylsalicylic acid) and its nonacetylated derivatives (eg, choline magnesium trisalicylate and salsalate). Propionic acid derivative-NSAIDs include ibuprofen and naproxen sodium. The para-aminophenol category is represented exclusively by acetaminophen. Since salicylates were available long before the newer traditional NSAIDs, the salicylates are therefore collectively grouped alone to distinguish them from the newer NSAIDs. Acetaminophen, at one time considered to be in a class removed from the NSAIDs, is now included within this group although it is a poor NSAID as regards its anti-inflammatory effects. Its action is limited to inhibition of prostaglandins centrally.²¹ This will be discussed subsequently in greater detail. Clinical profiles of the available OTC analgesics are summarized in Table 3.

NSAIDs are the most frequently prescribed analgesics for management of arthritic and musculoskeletal pain of mild to moderate intensity.³¹ As a class, they are the most commonly used pharmacologic agents worldwide,^32-34 with annual worldwide sales estimated to exceed $20 billion.³⁵ An estimated 30 billion nonprescription doses of NSAIDs are consumed each year in the United States³⁶ by 13 million individuals with osteoarthritis or rheumatoid arthritis.¹⁸

OTC NSAIDs are absorbed rapidly following oral administration. They achieve peak serum concentrations within 15 minutes to 2 hours, depending on the dosage form and product formulation. The drugs are bound to protein, primarily albumin, to greater than 90%, and are metabolized mainly by hepatic enzymes then excreted as metabolites via the kidneys. Their elimination half-life is a primary point of difference, ranging from 2.1±0.3 hours for ibuprofen to 14±2 hours for naproxen following a single oral dose.²¹

All NSAIDs possess analgesic, antipyretic, and anti-inflammatory effects. Since pain relief is proportional to dose and the drugs reach a ceiling for maximum activity, analgesic tolerance does not appear to occur. They do not alter the perception of sensory modalities other than pain.21 The OTC NSAIDs are indicated for short-term treatment of acute pain of mild to moderate intensity.³⁷

A review of adult medication use data from the 1999-2000 National Health and Nutrition Examination Survey (NHANES) revealed that 20% of US adults used nonprescription or prescription non-narcotic analgesics nearly every day for at least a month at some point during their lifetime.³⁸ Moreover, 14% of US adults were currently using analgesics frequently: 8%, aspirin; 3%, non-aspirin NSAIDs; 3%, acetaminophen. Three-fourths of aspirin users (which includes its use in cardioprotection), 46% of non-aspirin NSAID users, and 63% of acetaminophen users were long-term (frequent monthly) users (1-plus years). Seven percent of frequent monthly analgesic users reported taking two or more analgesics nearly every day during the month. Most of this frequent use was by older adults and non-Hispanic Caucasians. The study authors concluded that because frequent monthly non-narcotic analgesic use, especially of drugs available without prescription, is so widely prevalent among US adults, healthcare providers should intensify their awareness of this trend and routinely monitor nonprescription as well as prescription analgesic use in their patients to prevent adverse drug effects and inappropriate use.

Another investigation commented on the frequency and indications for OTC NSAID use, and the extent to which the public is aware of the products’ safety.³⁹ Investigators analyzed the responses of 9062 patients who were questioned as part of a Roper survey conducted in 1997, and a National Consumers League (NCL) survey conducted in December 2002. Ibuprofen-based products were the most frequently used OTC analgesics in both surveys. Seventeen percent of respondents in the Roper survey used NSAIDs, with 38% using both prescription and OTC products. Forty-six percent of exclusive OTC product users believed OTC NSAIDs were safer, while 56% of exclusive users of prescription NSAIDs believed they were safer. Sixty percent and 29% of exclusive OTC users were neither aware of nor believed they were at risk for side effects from NSAIDs, respectively. Twenty-six percent of respondents used more than the dose recommended on the label (Table 4), and 22% believed warning symptoms would always precede NSAID-induced complications. In the NCL survey, 83% had used an OTC NSAID within the past year, with 15% reporting daily use. Forty-nine percent were not concerned about potential adverse effects. Thirty percent of respondents indicated there was less risk of adverse effects with OTC analgesics, while 44% consumed more than the recommended dosage on the label. The investigators summarized their belief that OTC NSAIDs are widely used, often taken inappropriately in potentially dangerous doses, and users are frequently unaware of their potential for adverse effects. They urged strong educational intervention directed toward both patients and physicians.

Ibuprofen
Ibuprofen was the first propionic acid derivative NSAID to come into general use in the United States. Following a decade of use as a prescription drug, ibuprofen was switched to OTC status in 1984.^40,41

Since its switch to OTC status, numerous clinical trials have demonstrated that ibuprofen has a good risk-benefit ratio and is well suited for use as a nonprescription analgesic. It is generally well tolerated for treatment of acute pain.^42,43 To illustrate, the safety of single doses of nonprescription-strength ibuprofen was evaluated by examining documented adverse effects reported in 2579 patients representing 15 double-blind, randomized, controlled trials of the drug to treat various common painful conditions.⁴⁴ All study designs included placebo and acetaminophen arms. Eight hundred seventy-eight subjects received ibuprofen 200 mg or 400 mg, 849 received acetaminophen 650 mg or 1000 mg, and 852 received placebo. The overall frequency of adverse effects was comparable: ibuprofen 2.4%, acetaminophen 3.2%, and placebo 2.1%. Upper GI upset ranged from 0.8%-0.9% of subjects in all groups. These outcomes, demonstrating near equal efficacy and safety to acetaminophen, have been confirmed in other clinical trials.

Naproxen Sodium
Approved as a prescription drug in the United States in 1982, naproxen was made available for nonprescription use in 1994.41,45 Naproxen is approximately 20 times more potent than aspirin, while ibuprofen, fenoprofen, and aspirin are roughly equipotent as COX inhibitors. While there are limitations to the data, in comparative studies naproxen was considered the best tolerated of the chemical class followed by ibuprofen and fenoprofen.²¹ The efficacy and tolerability of naproxen have been established over many years of clinical use, and it can therefore be considered as a first-line treatment for osteoarthritis, other rheumatic diseases, and various pain states.46
OTC products contain the sodium salt of naproxen because it dissolves more rapidly in gastric juices and is absorbed more quickly than the free chemical. This results in a quicker onset of analgesic effect. Naproxen is distinctive from ibuprofen in that it is administered as the pure-active (S) enantiomer. Ibuprofen is administered as the racemic (R) mixture, which means that half of the drug dose consists of the inactive enantiomer, that is gradually converted to the active (S) form.

Ibuprofen vs. Naproxen Sodium
Schiff and Minic compared the two OTC NSAIDs for analgesic efficacy and safety in patients with osteoarthritis of the knee.²⁸ In two identical multicenter, randomized, double blind, placebo controlled, parallel-design studies, patients aged ≥25 years were randomized to daily doses of naproxen sodium 660 mg (440 mg in patients ≥65 years), ibuprofen 1200 mg, or placebo, for 7 days. Both naproxen sodium and ibuprofen were clinically effective at relieving pain compared with placebo (Figure 3). From the figure it can be seen that both treatments reduced the mean symptom score by 30%-45%, compared with 20%-25% reduction with placebo. Naproxen sodium significantly improved all seven symptoms compared with placebo, while ibuprofen significantly improved five of the symptoms. For patients aged ≥65 years, naproxen sodium was significantly superior to placebo in relieving all symptoms except pain on weight-bearing; ibuprofen significantly reduced day pain only. For daily pain diary evaluations, both analgesics effectively reduced all six symptoms. There was a trend toward higher efficacy for nighttime pain with naproxen sodium compared with ibuprofen. There were no significant differences in adverse events between groups.

Figure 3. Inhibition of COX-1/COX-2 by NSAIDs.

Aspirin
Aspirin was introduced into medicine in 1899, after sodium salicylate had been in use for nearly a quarter-century as a successful remedy for rheumatic fever, then later gout.¹⁷ The type of pain aspirin controls is pain of low to moderate intensity that arises from integumental structures, especially arthralgia, headache, and myalgia. Aspirin and other salicylates are widely used for pain relief and long-term use does not lead to tolerance or addiction. The drugs alleviate pain by virtue of a peripheral action to inhibit the COX enzyme, as discussed subsequently. Direct effects on the CNS also may be involved.²¹

Aspirin is widely used without medical supervision. The drug has unique pharmacologic properties that distinguish it from other members of the NSAID group. The best known and most relevant, as mentioned previously, is that aspirin irreversibly acetylates a serine residue (Ser529) that is near, but not inside, the COX catalytic site.^21,22,47 This blocks access of arachidonic acid into the catalytic site to inhibit formation of PGH₂ (and its product TXA₂) for the lifetime of the platelet (platelets are anucleate and therefore cannot regenerate protein). Data from randomised, controlled clinical trials have clearly demonstrated that because of this action, aspirin reduces both primary⁴⁷ and secondary⁴⁸ risk of serious adverse cardiovascular events. Aspirin, therefore, is an exception to any “class effect” of increased risk for serious adverse cardiovascular events that may exist with traditional NSAIDs.⁴⁹

In contrast to aspirin, traditional NSAIDs are competitive, reversible inhibitors of platelet COX-1, which results in reversible inhibition of TXA₂ formation.⁵⁰ For platelet aggregation to be impeded, platelet production of TXA₂ must be inhibited to greater than 95% extent.⁵¹ Traditional NSAIDs do not bind irreversibly to the serine residue and therefore are eliminated from the residue quickly. Since traditional NSAIDs do not cause significant inhibition of platelet TXA₂, this permits platelets to continue aggregating even during the NSAID dosing interval. In contrast, naproxen differs from the traditional NSAIDs in that it has a more extended half-life, leading to more sustained platelet inhibition.⁵²

Acetaminophen
Acetaminophen (paracetamol; N-acetyl-p-aminophenol) is the active metabolite of phenacetin.²¹ Phenacetin, a coal tar derivative of the highly toxic antipyretic acetanilide, replaced acetanilide in therapy in 1887. Phenacetin was withdrawn from use as an OTC analgesic in the United States in the late-1970s when implicated in analgesic-abuse nephropathy. Although acetaminophen was first used as an analgesic in 1893, it did not gain in popularity until 1949 after it was identified as the major active metabolite of both acetanilide and phenacetin.²¹

Acetaminophen is an effective analgesic, but differs from aspirin and the traditional NSAIDs in its weaker anti-inflammatory activity. To categorize acetaminophen as an NSAID may conflict with the thinking of some health care professionals whose classic pharmacology classes taught that acetaminophen is without anti-inflammatory action. However, acetaminophen is a prostaglandin inhibitor in intact cells.53,54 Acetaminophen reduces inflammation following oral surgery.⁵⁷ In one dental study, acetaminophen 1000 mg four times daily exerted greater anti-inflammatory activity than naproxen 500 mg two times daily on the third postoperative day following third molar extraction.⁵⁵ In a separate trial, ibuprofen 600 mg four times daily was compared to acetaminophen 1000 mg four times daily.⁵⁶ Ibuprofen failed to exert greater anti-inflammatory activity than acetaminophen with postoperative swelling and secondary pain as indicators of inflammation. The outcome from these and other findings relative to acetaminophen inhibition of selective prostaglandins suggests that the drug should share the same class warnings about potential adverse cardiovascular events as now required for NSAIDs.

Acetaminophen has a similar time-response curve as aspirin on modifying pain.²¹ Acetaminophen has gained limited favor among some clinicians and patients because of reports of adverse effects on the GI tract identified with aspirin and NSAIDs.⁵⁷ However, acute overdosage with acetaminophen can lead to severe, fatal hepatic damage as its primary toxicity.⁵⁸

Choosing an OTC Analgesic
There may be no definitive advantage to any one of the OTC analgesics when extent of acute pain relief is the sole determinant being assessed. Superior pain management may be suggested with one agent over another, but many of these investigations involve single doses or treatment of acute pain such as toothache. Others report on different treatment outcomes, which makes direct comparisons of activity difficult to assess. Major differences between the available OTC NSAIDs are confined to patient tolerability and pharmacokinetic considerations such as duration of action.

Several points need to be considered when choosing an OTC analgesic. One important pharmacokinetic difference is in their half-lives. Aspirin, with a plasma half-life of 15 minutes, and ibuprofen and acetaminophen, with half-lives of about 2 hours, must be administered every 4-6 hours. Naproxen has a half-life of nearly 14 hours and may be administered every 8-12 hours. A longer half-life may be preferred because of greater dosing convenience. At the same time, the choice of agent is often empirical and depends on the individual’s response to therapy. Cost is an important factor especially for agents that, with physician guidance, will be taken over an extended period.

Numerous clinical investigations have been undertaken in attempt to identify advantages of one drug over the others. For example, one mail survey evaluated the treatment preferences of 1799 patients with osteoarthritis, rheumatoid arthritis, or fibromyalgia.⁵⁹ About 37% of patients who had taken acetaminophen believed it to be moderately or very effective, while the majority, about 63%, indicated that it was not effective or was only slightly effective. When both effectiveness and adverse effects were considered together, 25% of the patients had no preference, 14% preferred acetaminophen, and 60% preferred NSAIDs. The study authors concluded that similar patient preferences were noted across all categories of patients and disease severity. They wrote that “… there would hardly ever be a reason to recommend acetaminophen over NSAIDs, since patients generally preferred NSAIDs and fewer than 14% preferred acetaminophen.”

Pincus and coworkers reported results of two randomized, placebo controlled, crossover, double-blind clinical trials.60 In Study-1, 524 patients and in Study-2, 556 patents age ≥45 years with osteoarthritis of the knee or hip were enrolled and randomized to receive acetaminophen 1000 mg four times a day, celecoxib 200 mg/day, or placebo for 6 weeks. Following a washout period, patients were reassigned to alternate therapy for an additional 6 weeks. Celecoxib was more efficacious than acetaminophen in both groups in both studies, and acetaminophen was more efficacious than placebo. Patient preferences for therapy were 53% celecoxib versus 24% acetaminophen in Study-1, and 50% versus 32% in Study-2; 37% acetaminophen versus 28% placebo in Study-1, and 48% versus 24% in Study-2. Adverse effects and treatment tolerability were similar.

Nonprescription doses of naproxen sodium and acetaminophen were compared with placebo to determine their efficacy and safety in osteoarthritis of the knee.⁷ In two identical multicenter, randomized, double-blind, placebo-controlled, parallel-design studies, patients (mean age 60.6 years) were randomized to daily doses of naproxen sodium 660 mg (440 mg in patients ≥65 years), acetaminophen 4000 mg, or placebo for 7 days. In total, 465 patients were included in the pooled analysis of the data.

Acetaminophen provided significantly greater improvement in day pain compared with placebo (Figure 4). Naproxen sodium provided significantly greater improvement in pain at rest, on passive motion, on weight-bearing, stiffness after rest (morning), day and night pain compared with placebo, and significantly greater relief from resting pain than acetaminophen. Daily evaluation revealed that naproxen sodium afforded superior pain relief to acetaminophen and was significantly better than acetaminophen at modifying difficulties in walking and in bending, lifting, and shopping. Naproxen sodium and acetaminophen were both significantly more effective than placebo in improving mobility level, household tasks, and walking and bending. Adverse GI effects were generally mild and included dyspepsia, upset stomach, nausea, and loose stools. Both NSAIDs had similar safety profiles to placebo. The investigators noted that “At nonprescription doses, naproxen sodium to a higher extent and acetaminophen to a lesser extent were efficacious in reducing the pain associated with osteoarthritis of the knee.” They concluded that “… naproxen sodium is an alternative in the initial treatment of osteoarthritis and may be preferred to acetaminophen as first-line therapy in patients with moderate or severe pain.”

Figure 4. Symptom intensity differences from baseline for 7 pain assessments for the total efficacy population following treatment with naproxen sodium, ibuprofen, or placebo.²³

A meta-analysis of seven published articles that described treatment efficacy in 1252 subjects with symptomatic hip or knee osteoarthritis (752 on NSAID and 500 on acetaminophen) concluded that NSAID therapy was statistically superior in reducing pain at rest and walking compared with acetaminophen.⁴⁰ Drug safety, measured by discontinuation due to adverse events, was not statistically different between NSAID and acetaminophen users.

A 2006 Cochrane review analyzed the published data on acetaminophen in treatment of osteoarthritis.²⁵ The review concluded that acetaminophen is an effective and relatively safe treatment for osteoarthritis; however, acetaminophen is less effective than traditional NSAIDs for pain reduction, global assessments of efficacy (patient and investigator), and improvements in functional status.

The 1996 American College of Rheumatology (ACR) treatment guidelines for osteoarthritis recommended acetaminophen as first-line pharmacologic therapy for osteoarthritis. This recommendation was modified in the updated 2000 (ie, current) guidelines, which stated that acetaminophen be considered as a reasonable initial treatment for mild-moderate osteoarthritis pain, but for treatment of moderate to severe osteoarthritis pain, NSAIDs may be considered as an alternative initial therapeutic approach.61 The newer recommendation was based in part on current evidence that suggested traditional NSAIDs were actually superior to acetaminophen in management of osteoarthritis-related pain.⁶² The Canadian Consensus Guidelines recommend NSAIDs as treatment of first choice for moderate to severe osteoarthritis.⁶³

CONCERNS RELATIVE TO REPORTED NSAID-INDUCED ADVERSE CARDIOVASCULAR EVENTS

Recent Events in NSAID Therapeutics
Rofecoxib (Vioxx) was voluntarily withdrawn from the market in September 2004 following reports that people taking it in a long-term controlled clinical trial had an increased risk of serious adverse cardiovascular events compared to placebo. In early-December 2004, FDA required a “black box” warning for valdecoxib (Bextra),⁶⁴ and in April 2005 asked its manufacturer to withdraw marketing of valdecoxib.65,66 Meanwhile, additional data were made available from various controlled clinical trials involving coxibs that further seemed to support an increased risk of cardiovascular toxicity for coxibs compared to placebo.

The strongest data for an increased risk of serious adverse cardiovascular events with rofecoxib were derived from the long term placebo-controlled trial called the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial,⁶⁷ designed to evaluate the efficacy of rofecoxib 25 mg once daily in preventing the recurrence of large bowel polyps in 2600 patients with a history of colorectal adenomas. Three-year data from this study showed that after 18 months of treatment, a relative risk for serious adverse cardiovascular events of approximately 2-fold greater intensity was noted for rofecoxib compared to placebo. Relative risk is defined as the cumulative risk in the treatment group (eg, number of events per number of individuals in this group) divided by the cumulative risk in the control group. It should be noted that the adverse cardiovascular effect of rofecoxib did not begin to appear in the APPROVe trial until after about 18 months of treatment. However, further analysis of the data by an independent source showed that patients are at increased risk even if rofecoxib is taken only for a few months.⁶⁸

A long-term controlled clinical study that compared rofecoxib to a traditional NSAID, naproxen, in 8076 patients was the Vioxx GI Outcomes Research (VIGOR) trial.⁶⁹ The study focused on patients aged 50 years or more. Patients received rofecoxib (n=4047) or naproxen (n=4029) for up to 12 months. Rofecoxib resulted in a hazard ratio of approximately 2 compared to naproxen based on the composite endpoint of death, MI, or stroke. The response to rofecoxib began to separate from that of naproxen after approximately 2 months of treatment. Overall, the rate of MI was four times higher in patients taking rofecoxib than in those taking naproxen. The result of subsequent analysis by FDA officials indicated the difference in risk was a 5-fold increase.⁷⁰

The strongest data to support the contention of an increased risk of serious adverse cardiovascular events for celecoxib (Celebrex) was provided by the Adenoma Prevention with Celecoxib (APC) trial in patients at risk for recurrent colon polyps.⁷¹ There was a 2- to 3-fold increased risk of adverse cardiovascular events noted for celecoxib compared to placebo after a mean duration of 33 months of treatment. The study results showed evidence of a dose response relationship, with a hazard ratio of 2.5 for celecoxib 200 mg twice daily and 3.4 for celecoxib 400 mg twice daily compared to placebo, for a composite endpoint of death from cardiovascular causes, MI, or stroke. The hazard ratio is defined as the ratio of the hazard rates from the treatment group relative to controls. The hazard ratio is often used interchangeably with the relative risk.⁷²

The Celebrex Long-Term Arthritis Safety Study (CLASS) was a long-term comparison of celecoxib to nonselective NSAIDs.⁷³ Celecoxib 400 mg twice daily was compared to diclofenac and ibuprofen in approximately 800 patients with osteoarthritis or rheumatoid arthritis. In contrast with VIGOR, there was no difference in serious adverse cardiovascular events between celecoxib and the two traditional nonselective NSAIDs. One major difference between CLASS and VIGOR was that the studies used different non-aspirin NSAIDs as comparators. Another difference was that VIGOR enrolled only patients with rheumatoid arthritis among whom elevated risk for MI has been noted previously.^74,75

To date, there have been no long-term controlled clinical investigations comparing valdecoxib to placebo or traditional NSAIDs. The results from two short term placebo-controlled trials with intravenous parecoxib (pro-drug for valdecoxib) followed by oral valdecoxib in patients immediately following coronary artery bypass graft surgery indicated that valdecoxib increased the incidence of serious cardiovascular events approximately 2-fold compared to placebo.^72,76

No data from controlled clinical trials pertaining to cardiovascular safety of etoricoxib, another investigational COX-2 selective drug, in the United States have been published to date. A case control study utilizing a general practice database in the United Kingdom noted a similar risk of MI for celecoxib, rofecoxib, ibuprofen, and naproxen.⁷⁷ A retrospective study in patients with congestive heart failure found reduced morbidity and mortality in patients treated with celecoxib rather than with rofecoxib or traditional NSAIDs.⁷⁸

In the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), lumiracoxib 400 mg once daily was compared with naproxen and ibuprofen for 1 year in approximately 18,000 patients with osteoarthritis.⁷⁹ The study was designated as two separate sub-studies with planned primary analysis to be the combined lumiracoxib groups compared to the combined naproxen and ibuprofen groups. The cardiovascular endpoint was based on the Antiplatelet Trialists Collaboration endpoint of nonfatal and silent MI, stroke, or cardiovascular death.⁴⁷ Randomization of patients occurred at the sub-study level rather than across the entire study group. Thus, the rates for serious adverse cardiovascular events in the lumiracoxib groups in the two sub-studies differed greatly: 1.1 events per 100 patient years in the naproxen sub-study versus 0.58 events per 100 patient years in the ibuprofen sub-study. It was noted that patients in the naproxen sub-study had a greater risk for adverse cardiovascular events when they were entered in the trial (12% of patients in the naproxen sub-study had a history of cardiovascular risk compared to 8% in the ibuprofen sub-study). The outcome event rates for naproxen and ibuprofen nonetheless were similar in the two sub-studies: 0.76 events per 100 patient years for naproxen and 0.74 events per 100 patient years for ibuprofen.

The TARGET data were also analyzed by sub-study. In the naproxen sub-study, a hazard ratio for serious adverse cardiovascular events of 1.44 was recorded for the comparison of lumiracoxib and naproxen. A hazard ratio of 0.79 was observed in the ibuprofen sub-study for comparison of lumiracoxib with ibuprofen for serious adverse cardiovascular events. There were no significant differences between lumiracoxib and the traditional NSAIDs in either sub-study. The study failed to clearly distinguish between lumiracoxib and traditional NSAIDs.

Even though there are limitations in the available data, overall there appears to be evidence from a small number of placebo-controlled trials to support the notion of an association with coxibs that puts people at increased risk of serious adverse cardiovascular events. It is unclear as to how significant or under what circumstances this association is.

FDA has concluded that there is a “class effect” for risk of increased cardiovascular events for all non-aspirin NSAIDs.⁸⁰ The issue may be clarified when data become available from long-term controlled clinical trials to clarify the true relationships. In a memorandum from the Director of FDA’s Office of New Drugs, naproxen was identified as the single NSAID for which there may be an exception from the implication of increased risk for adverse cardiovascular events.⁷²

CURRENT STATUS OF OTC NSAIDS RELATIVE TO ADVERSE CARDIOVASCULAR EVENTS

Because naproxen has been identified as a possible exception from the implication that it increases the risk for adverse events, the following is offered in its defense. Aisen and colleagues undertook a randomized, placebo-controlled study of naproxen in patients with Alzheimer’s disease.81 The trial randomized patients to 1 year of treatment with rofecoxib 25 mg daily, naproxen (as Aleve) 220 mg twice daily, or placebo. The study objective was to determine if there was an effect of NSAIDs on progression of underlying Alzheimer’s disease. Three hundred fifty-one patients were randomized: 122 to rofecoxib, 118 to naproxen, and 111 to placebo. No specific handling of cardiovascular events was undertaken and safety data were collected as part of the routine monitoring of the trial.

Serious adverse events of stroke/transient ischemic attack were reported in three patients on rofecoxib, three on naproxen, and one patient on placebo. Serious adverse events of myocardial infarction (MI) were noted in three patients on rofecoxib, none on naproxen, and one patient on placebo. Because the number of serious adverse events was small, there was no suggestion of an increased risk of cardiovascular events with naproxen.²⁴

Observational Studies
A number of observational studies have investigated the association between naproxen and risk of cardiovascular events.

Kimmel et al.—A hospital based, case-control study compared approximately 1150 cases of nonfatal MI with over 4000 controls.⁸² The study differed from others in that exposure information was determined directly from the subjects, a clear advantage over many other studies that used mail or telephone survey techniques. An objective of the study was to evaluate any interactions between aspirin and other NSAIDs with respect to the risk of MI.

The investigators reported a significant reduction in risk with other NSAIDs in the absence of aspirin use. For naproxen, an odds ratio of 0.48 was reported. That is, among patients not taking aspirin, current use of naproxen was associated with approximately 20%-70% reduction in the risk of MI compared with nonusers of NSAIDs. In patients already taking aspirin, there was no significant benefit of NSAIDs.

The authors discuss potential recall bias, but such a bias, if present, would tend to show a positive association between exposure and being a case. They theorized that cases were less likely to be exposed to naproxen than controls, thereby suggesting a possible underestimation of the true protective effect of naproxen. The overall conclusion was that nonaspirin NSAIDs may reduce the risk of MI.

Mamdani et al.—A cohort study was undertaken using information provided by an administrative healthcare database in Ontario.83 The primary objective was to investigate possible relationships between coxibs and naproxen on the risk of acute MI in elderly NSAID-naïve patients. Study authors compared medical records of users of celecoxib, rofecoxib, naproxen, and NSAIDs other than naproxen with a random sample of 100,000 control subjects who had not received these drugs. Nearly 6000 subjects had been exposed to naproxen, 1200 to rofecoxib, 15,000 to celecoxib, and 33,000 to a nonselective NSAID other than naproxen. The average age was approximately 75 years and patients were followed up to 1 year.

The authors estimated incidence rates of hospitalization for acute MI to be 9.6 per 1000 patient-years (naproxen), 10.7 per 1000 patient-years (celecoxib), 12.1 per 1000 patient-years (rofecoxib), and 8.2 per 1000 patient-years for controls. Compared to controls, the adjusted relative risk associated with naproxen use was 1.0. The authors concluded that there were similar nonsignificant relative risks for other exposed cohorts compared with the control group: celecoxib (0.9), rofecoxib (1.0), and non-naproxen NSAIDs (1.2). Overall, there was no increase in the short-term risk of acute MI among users of these drugs.

Rahme et al.—In a retrospective, case-control study, Rahme and coworkers evaluated the association between naproxen use and risk of acute MI in patients over 65 years of age.84 The study compared approximately 14,000 Canadian men and women hospitalized with an MI with the same number of controls. RAMQ and Med-Echo databases in Quebec were used for data.

The investigation revealed that concurrent chronic users of naproxen had a lower incidence of acute MI than concurrent chronic users of other NSAIDs (odds ratio, 0.64). In other words, patients undergoing concurrent chronic use of naproxen had a 14%-52% reduced risk of acute MI compared with users of other NSAIDs. Concurrent chronic exposure was defined as having received at least two prescriptions and with 60 or more consecutive days of prescription duration that covered or overlapped with the index date.

The two comparison groups (naproxen users and other NSAID users) were similar, thus reducing the potential for confounding. Study limitations included that the indication for NSAID use or important risk factors, such as cigarette smoking and obesity, could not be assessed. Concurrent use of OTC drugs including aspirin, naproxen, and ibuprofen, could likewise not be evaluated. None were believed likely to have had a major impact on the overall conclusions.

Solomon et al.—In a large retrospective case-control study, Solomon et al evaluated patients using information from databases of the New Jersey Medicaid or Medicare and Pharmaceutical Assistance for the Aged and Disabled programs.85 They identified 4425 cases of acute MI and used 17,700 control subjects who did not experience an acute MI during the study period. Exposure to an NSAID was defined as having received a prescription within 6 months prior to diagnosis of MI for cases, or within 6 months prior to the index date (date of hospitalization) for the controls. Data were controlled for clinical, sociodemographic, and health care use characteristics; age, gender, ethnicity; insurance statement medical history of hypertension, diabetes mellitus, and congestive heart failure. Overall, users of traditional (nonaspirin) NSAIDs had the same risk as nonusers of NSAIDs. Interestingly, naproxen use within the previous 6 months correlated with a significant decrease in risk of acute MI (odds ratio, 0.84) compared with nonusers of NSAIDs. When compared with ibuprofen, a similar benefit was noted in favor of naproxen. The study authors concluded there was a 16%-20% reduction in risk of MI in subjects on naproxen.

The authors indicated there was a potential limitation to the study: OTC use of NSAIDs. Since the study was conducted in low-to-moderate income patients who qualified for subsidized or free prescriptions, the authors felt that OTC use would not be widespread enough to influence the overall interpretation. Information on potential confounders such as lipids and smoking histories was also not available, but naproxen prescriptions were unlikely to be influenced by these. To minimize the potential confounding effect of OTC aspirin use, the authors excluded patients who they believed were likely to be managed with aspirin, for example those with coronary artery disease, cerebrovascular disease, and other similar afflictions.

Watson et al.—A retrospective study using data from the United Kingdom General Practice Research Database evaluated the risk of acute thromboembolic cardiovascular events (MI, sudden death, and stroke) in 16,937 patients with rheumatoid arthritis who were receiving naproxen.86 Patients were 40-79 years of age and excluded persons with a previous thromboembolic cardiovascular event or other medical pathologies that might confound the outcome, including cancer, vasculitis, coagulopathy, or alcohol or drug abuse at any time prior to onset of the study. Patients with a prescription for flurbiprofen, or an anticoagulant or antiplatelet agent during the year prior to the start of the study and/or 30 days or less prior to their index date, were excluded. A total of 809 cases (435 MI, ²⁷ sudden death, 347 cerebrovascular events) were matched with control patients with rheumatoid arthritis.

The study revealed that current users of naproxen experienced a reduced risk of acute thromboembolic cardiovascular events compared with nonusers of naproxen, odds ratio of 0.61. The odds ratio for past naproxen use was 0.87. Additionally, the study revealed a nonsignificant reduced risk of MI for current users of naproxen compared with nonusers with an odds ratio of 0.57. There was no protective effect reported for any other nonaspirin NSAID.

Graham et al.—Controversy continues to surround the issue of whether naproxen decreases the risk of serious coronary heart disease. Graham and coworkers examined data from the Kaiser Permanente databank.87 A total of 1,394,764 people aged 18-84 years who were treated with various NSAIDs during a 3-year interval contributed 2,302,029 person-years of observational time to the study cohort. The investigators reported 8143 cases of serious coronary heart disease, of which 2210 were fatal. For naproxen versus remote NSAID use, the adjusted odds ratio was 1.14. The conclusion was that there was no significant difference between naproxen and control drugs with respect to their ability to protect against serious coronary heart disease. Naproxen neither increased the risk for adverse cardiovascular events nor protected against them.

Juni et al.—Juni and coworkers recently published their findings from a review of 11 observational studies and presented their study results in a forest plot (Figure 5).⁶⁸ Their overall assessment was that the relative risk of MI associated with naproxen usage was 0.84 compared with both nonusers of NSAIDs and users of other NSAIDs. Naproxen use resulted in a small but significant cardioprotective effect. The results of their meta-analysis were later summarized in a commentary published in the Journal of the American Medical Association in which the author concluded that naproxen is the only NSAID that possesses cardioprotective activity, with an estimated risk reduction of MI of 14% (compared to 23% reduction by aspirin).^88,89

Figure 5. Forest plot showing the results of a meta-analysis of observational studies of naproxen and risk of myocardial infarction.⁶⁸

It should be noted that the duration of naproxen use is rarely ascertained from published studies. Therefore, the conclusions in the reports discussed above may not be applicable to chronic use of the drug. Moreover, even though the majority of clinical trials represent NSAIDs taken in prescription doses, the pharmacodynamics and therapeutic outcomes can be expected to apply to nonprescription doses as well.

FDA Recommendations
The FDA has ruled that the professional labeling for all prescription NSAIDs, including both coxibs and traditional drugs, be revised to include a boxed warning stressing the potential for increased risk of adverse cardiovascular events.⁷² The boxed warning should also include the well-established risk of serious GI bleeding. Additionally, the labeling for all NSAIDs should include a contradiction for use in patients immediately following coronary artery bypass grafting surgery.

The Agency has noted that ibuprofen and naproxen are currently available without a prescription for the short-term treatment of acute pain and that these nonprescription products should continue to be available to consumers. The Agency acknowledges that this would be the first time that products with a boxed warning in the prescription package insert would also be available for nonprescription use. The FDA was convinced that available data support the conclusion that short-term use of usual doses of the nonprescription NSAIDs, which are generally well below the maximum daily doses for the same active ingredient, and the duration of treatment are not associated with increased risk of serious adverse cardiovascular events. There was no signal detected for increased risk of serious adverse cardiovascular events in any of the short-term controlled clinical trials that were conducted to support approval of these agents for treatment of acute pain.⁷² The benefit versus risk profile for the OTC NSAIDs is therefore very favorable when they are used according to labeled instructions, and it is important to maintain a range of therapeutic options for the short-term relief of pain in the OTC market.

To encourage the safe use of nonprescription NSAIDs, the labeling for the products has been revised, and a template for labeling of adult packages of products of OTC NSAID products is shown in Figure 6.^37,90 Labeling includes more specific information about the potential cardiovascular and gastrointestinal risks, instructions about which patients should seek the advice of a physician before using the drugs, and stronger reminders about limiting the dose and duration of treatment as stated within the package instructions unless advised otherwise by a physician. The restriction for naproxen that limited daily doses to 440 mg for persons ≥65 years of age has been removed. The same dosage, in the absence of specific contraindications to use, is recommended for all adults, regardless of age. Current labels for all OTC NSAID products state that persons should ask a doctor if they have reached age 60 or older (see Figure 6).

Figure 6. Template for labeling of OTC adult drug products containing an NSAID.⁴²

PATIENT COUNSELING ON NONPRESCRIPTION NSAIDs

Counseling patients with osteoarthritis and, when appropriate, their family members, is an integral component of the treatment plan.^61,91 There is little doubt about the reliability and effectiveness of counseling in pain management techniques for patients in pain, and it provides a valuable supplement to current health care practices. The majority of patients are unaware of correct doses, proper administration time or technique, or potential risks associated with use of OTC analgesics.^92,93 One disturbing report confirmed that nearly 50% of patients with musculoskeletal conditions including osteoarthritis do not fully comply with medication requirements.⁹⁴

Because their requests for information or assistance in choosing a drug of choice may not be clearly expressed, interpreting what patients want or need can be of great difficulty in the counseling process. Moreover, approximately half of the requests are made by another individual on behalf of the person in need. The high number of adults reporting multiple analgesic use nearly every day, and the large number who take more than recommended amounts of the drugs (see Table 4) highlight the need for pharmacists to closely monitor nonprescription drug product use as well as prescription analgesic use and for increased patient education. The conclusion of a recent review of 42 published studies of advice given in community pharmacies confirmed, unfortunately, that the quality and quantity of advice was highly variable.⁹⁵ It is therefore important that pharmacists identify at minimum, what patients expect from their treatment and what they need to know in order to receive maximum benefit. Information provided in Table 5 can be given to patients to help them interpret the products’ labeled instructions (see Figure 6) clearly.

Table 5. Patient Advice for OTC Analgesics^* 

• Take this medicine with at least 6 oz of water or other liquid.
• Do not take more than one kind of pain medicine at a time. Talk to your pharmacist or healthcare provider if you have questions.
• Some OTC products that are not readily identified as pain relievers may still contain OTC analgesic drugs (eg, multisymptom cold products, sleep aids). Be sure to read the labels of all OTC products, and do not mix products without talking with your pharmacist or doctor first.
• Do not give this medicine to children younger than the age indicated on the label unless directed to do so by your doctor.
• Do not wait until your pain has become very severe before taking your OTC pain reliever. Waiting too long may make it harder to get relief. Instead, take your medicine at the first sign of pain.
• Store this product at room temperature; avoid excessive heat and moisture.
• Ask a physician before taking this medicine if you have ever had a serious side effect from any pain reliever.
• Follow the directions on the product’s label carefully, unless your doctor directs you otherwise.

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^*Appropriate to convey to patients in addition to labeled instructions (see Table 4).

SUMMARY

It is now generally believed that pain of osteoarthritis is a result of inflammation. Patients with osteoarthritis mayrely on nonprescription analgesics to manage their pain. Of salicylates, traditional NSAIDs, and acetaminophen, many people in pain will choose a product containing ibuprofen or naproxen because of their belief that these traditional NSAIDs excel over acetaminophen in treatment of mild to moderate pain of osteoarthritis. Used as directed, NSAIDs are safe and effective for self-administration of mild to moderate pain. These outcomes can be assured when pharmacists council patients on their correct use. The jury is still out as regards whether NSAIDs increase a person’s risk of adverse cardiovascular events. Considerable evidence is available that shows naproxen may actually lower the risk of these events; however, additional study is warranted.