US Pharm. 2009;34(4)(OTC Trends Suppl):3-7. 

During a routine diabetes management follow-up in an indigent health care setting, an illiterate patient reports that he uses "a handful" of ibuprofen every 3 to 4 hours and "a handful" of Tylenol every 2 to 3 hours for pain. If neither of these provides pain relief, he will occasionally take "a few" Aleve. Employed as a clerk in a convenience store, he states that he has to work to feed his family, but if he can't take care of the pain in his legs, he can't work. Therefore, he purchases nonprescription pain relief while at work and self-medicates until there is pain alleviation. Upon further questioning, the patient reports stomach pains and blood in his stool. The pharmacist can certainly assist the patient in understanding proper dosage administration of these agents and the adverse effects he is now experiencing, but proper consultation with a pharmacist prior to use more than likely would have prevented this situation. Scenarios such as this underscore the importance of pharmacist consultation for patients selecting to self-medicate with nonprescription analgesics. The widespread use and accessibility of nonsteroidal anti-inflammatory drugs (NSAIDs) may allow consumers to erroneously assume the safety of these medications. However, the recommendation of an NSAID still requires vigilance regarding drug interactions and adverse effects, particularly in high-risk patient populations.1

The Slone Survey, a population-based telephone survey administered from 1998 to 1999, demonstrated the widespread use of nonprescription products for self-treatment of pain, inflammation, and fever. 2 It revealed ibuprofen, aspirin, and acetaminophen as three of the top four most commonly used entities in the nonprescription market, taken by about 17% to 23% of the population. Similarly, the National Center for Health Statistics found NSAIDs listed within the top two most commonly used medications throughout the United States for 2003-2004 reports.3,4 These data do not delineate prescription versus nonprescription NSAID use, but they do indicate ibuprofen as the most frequently mentioned pain reliever.  

Indications and Actions

Available nonprescription NSAIDs include aspirin, ibuprofen, and naproxen. Ketoprofen was previously available as a nonprescription agent; however, due to decreased demand, all current formulations are by prescription only.5,6 Nonprescription NSAIDs are primarily used for their analgesic, anti-inflammatory, and antipyretic effects, but low-dose aspirin may also be used prophylactically for cardioprotection.7,8 The beneficial and adverse effects of these agents are attributed to their ability to inhibit the cyclo-oxygenase (COX) enzymes, COX-1 and COX-2, which play a key role in the conversion of arachidonic acid to prostaglandins and thromboxanes.7-9 Unlike the other NSAIDs, aspirin irreversibly inhibits COX-1, allowing inhibition of thromboxane synthesis, which in turn reduces platelet aggregation.8 Inhibition of COX-1 by other NSAIDs is reversible and dependent on the drug and dose. At this time, it appears only aspirin confers cardioprotection.8  

Administration and Dosage

When an NSAID is considered an appropriate recommendation for self-care, counseling should include time limitations for use and proper dosage administration according to age or weight. Patients who are using NSAIDs for the self-treatment of pain or inflammation should limit the use of these products to 10 days.10,11 It is important to note that ibuprofen typically takes from a few days to 2 weeks to elicit a response in the treatment of inflammation, which may extend past the recommended use of the product for self-care.5,10 In this case, provider referral may be necessary. When recommending self-care for fever, the duration of use prior to provider referral should not exceed 3 days. The fever-lowering effects of ibuprofen can be seen within 1 hour, but it is also necessary to discuss with patients that complete resolution of a fever may take 24 hours.

Ibuprofen

Ibuprofen is FDA-approved as a nonprescription product for ages 6 months through adulthood and is available in various formulations, including tablets, capsules, chewables, suspension, and drops.5 Pediatric dosing should be based on 5 to 10 mg/kg of body weight. Specific pediatric ibuprofen formulations include oral drops (40 mg/mL) for ages 6 months to 3 years, suspension (100 mg/5 mL) for ages 2 to 11 years, chewable tablets (50-100 mg) for ages 4 to 11 years, and junior-strength tablets (100 mg) for ages 6 to 11 years. TABLE 1 provides more specific dosing based on age and weight for each of these pediatric formulations. Care should be taken to ensure a correct weight-based dose is used, as well as an appropriate measuring device for liquid formulations.

Some studies in the pediatric population have concluded that ibuprofen, particularly at a dose of 10 mg/kg, is superior to acetaminophen as an analgesic and antipyretic, but literature reviews typically conclude equal efficacy between the two agents.12 However, due to its low risks for adverse effects and drug interactions, acetaminophen remains the preferred agent in the pediatric population.

Adult formulations of ibuprofen are all available in 200-mg dosages.5,10 When dosing ibuprofen as an antipyretic or analgesic, the adult dose is 200 mg every 4 to 6 hours as needed, up to a maximum of 1,200 mg/day. However, when using ibuprofen for a migraine, it is dosed as 400 mg (2 capsules or tablets) at the onset of the headache, with provider intervention if symptoms worsen or persist. Doses greater than 400 mg/day should not be recommended for self-care of migraines.

Sometimes, pharmacists may encounter patients who have been given the recommendation to alternate dosing of ibuprofen and acetaminophen, either for the pediatric or the adult patient. Though there are no conclusive data to support the efficacy or safety of alternating regimens, some providers still recommend this practice.13 The concern with this practice is confusion over dosages and administration times, which could lead to an increase in the risk of adverse effects, including renal toxicity, particularly in a dehydrated patient.13,14 There have been studies to show some benefit to this practice, including a sustained antipyretic effect and less gastrointestinal irritability when compared with ibuprofen monotherapy. However, until further research is available, pharmacists should refrain from recommending alternating regimens for self-care. 

Naproxen

Self-care with naproxen is approved for adolescents and adults only, with a recommended age of 12 and older.5,11 Naproxen is available nonprescription in 200-mg tablets, caplets, and gelcaps, equivalent to 220 mg naproxen sodium. Dosing recommendations are specified for patients age 12 to 65 as one to two tablets, caplets, or gelcaps taken initially and then only one every 8 to 12 hours thereafter, with a maximum dosage of 660 mg/day. However, no more than 440 mg should be taken within an 8- to 12-hour period. The maximum dosage in individuals ages 65 and older is 440 mg/day, with the recommendation of only one 220-mg formulation every 12 hours. 

Aspirin

Aspirin is available nonprescription in immediate-release formulations and enteric-coated formulations in strengths ranging from 81 mg to 500 mg.5 Patients are sometimes confused between film-coated and enteric-coated aspirin, which are not the same. Film-coated tablets are more rapidly absorbed, with peak plasma salicylate levels occurring within 45 to 120 minutes as compared with 8 to 14 hours for enteric-coated tablets.

Traditionally, aspirin was used in pediatric populations, but the risk of Reye's syndrome has prompted the recommendation to limit its use to individuals age 15 and older. 5 Some literature does suggest aspirin avoidance through age 18, but it appears that a general consensus is age 15. Not only can age-appropriateness of aspirin use be confusing, but the appropriate dose can vary according to its intended use. Very few providers recommend aspirin for pain or fever, as there are other alternatives with fewer adverse effects. However, for those patients who choose to use aspirin for these purposes, the dose is 325 mg to 650 mg every 4 hours as needed with a maximum daily dose of 4 g. Pharmacists should always encourage utilization of the lowest effective dose of aspirin.

Most notably, aspirin has gained widespread routine use as prophylaxis of stroke and/or myocardial infarction (MI).5 Aspirin used for long-term MI prophylaxis should be dosed as 75 mg to 162 mg once daily, with doses less than 100 mg per day recommended in patients with risk factors for bleeding. Aspirin doses used for stroke prophylaxis range from 50 mg to 325 mg per day, depending on previous history and risk factors. Aspirin also takes center stage in the medicine cabinet for the emergency management of suspected acute coronary syndrome (ACS). Interim to hospital arrival, patients should immediately chew and swallow 160 mg to 325 mg of a nonenteric-coated tablet. Follow-up of aspirin used for suspected ACS is with emergency care only. Further specifications for dosing for cardiovascular and cerebral events is well documented in the literature, but is beyond the scope of this article. 

Adverse Effects Associated With NSAIDs

Gastrointestinal: Between 1998 and 2001, the FDA's Adverse Event Reporting System identified 279 cases of gastrointestinal bleeding associated with the use of nonprescription NSAIDs. Of these cases, 197 were attributed to ibuprofen, ketoprofen, or naproxen use, and 82 were attributed to aspirin use.7 The following risk factors for gastrointestinal bleeding with NSAID use, either prescription or nonprescription, have been identified5,7,15:

* Use of concomitant medications such as myelosuppressive chemotherapy, corticosteroid therapy, anticoagulant therapy, and/or other NSAIDs

* Age >60 years

* High dosage

* Previous history of gastrointestinal bleeding

* Concomitant use of alcohol and/or tobacco

When the benefits of chronically using a NSAID outweigh the risks, only misoprostol 400 mcg to 800 mcg is FDA-approved for prevention of gastrointestinal distress, with 800 mcg being the only dose to demonstrate a reduced risk of ulcer complications.16,17 However, because misoprostol is a known abortifacient and causes diarrhea even at lower doses, it is not often prescribed for prophylaxis of gastrointestinal adverse effects associated with NSAID use. Both a proton pump inhibitor, such as omeprazole, and a double dose of a H2 blocker (i.e., 300 mg of ranitidine twice daily) have demonstrated efficacy in the prevention of gastric and duodenal ulcers associated with NSAID use and thus may be a more prudent recommendation for gastrointestinal protection.  

Cardiovascular: The gastrointestinal effects associated with NSAID use are typically the focus of most literature, though cardiovascular and renal effects are well-known. NSAIDs may cause exacerbation of congestive heart failure (CHF), cardiovascular thrombotic events, MI, or stroke, all of which may be fatal.18 Most of these effects on cardiovascular homeostasis are thought to be attributable to the effect of NSAIDs on renal function.

It appears that those at greatest risk for cardiovascular disease associated with NSAID use include long-term users, patients with previous cardiovascular disease, patients using concomitant NSAID and antihypertensive or diuretic therapy, and elderly patients.8,10 Elderly patients may be at more risk due to the age-related decline in cardiac and renal function, and also because of the increased propensity for polypharmacy due to analgesic treatment for other disease states such as osteoarthritis. Since risks may outweigh benefits, it is of practical value to assess risk factors for NSAID-related cardiovascular events. If NSAIDs are deemed necessary in at-risk patients, monitoring of blood pressure, weight gain, dyspnea, edema, and other symptomatic deterioration should be instigated at regular intervals during treatment.8,19

Current literature suggests that NSAIDs do not increase the risk of first-occurrence heart failure, but do substantially increase the risk of relapse of pre-existing heart failure, particularly in patients using concomitant diuretic therapy.8,20,21 NSAIDs promote sodium and fluid retention, which can be detrimental in the patient with heart failure. However, when combined with a loop diuretic, NSAIDs produce a blunted diuretic response, leading to further fluid retention.8,18 Information regarding agent-specific induction of NSAID-related CHF exacerbation is conflicting.8,9,22 Some reports have suggested that NSAIDs with longer half-lives, such as naproxen, may be associated with a higher risk than those with shorter half-lives, such as ibuprofen, whereas other reports demonstrate no difference between the two NSAIDs. Regardless, the highest risk for hospitalization for CHF following NSAID initiation is within the first few days of use, with the majority occurring within 30 days.19,22

A general consensus in literature suggests that NSAIDs do increase blood pressure, most notably in treated and untreated patients with pre-existing hypertension, but the extent of blood pressure elevation can be variable.8,18 With the exception of the elderly, normotensive patients should experience minimal changes, if any, in blood pressure regulation.8 As with exacerbation of CHF, a contributory difference to elevations in blood pressure among the different NSAIDs has not been firmly established, but some data do note a higher risk with the use of naproxen.8 As an additional blow to the hypertensive patient, NSAIDs can also antagonize the blood pressure-lowering effects of antihypertensive therapy, including thiazides, loop diuretics, alpha-adrenergic blockers, beta-adrenergic blockers, and ACE inhibitors.8,18 This interaction occurs because both NSAIDs and antihypertensives, with the exception of calcium channel blockers, have prostaglandin-mediated mechanisms.8 Though changes in blood pressure could be minimal, even slight increases in systolic blood pressure of 3 mmHg can increase the risk of CHF by 10% to 20%, stroke by 15% to 20%, and angina by 12%.8 Obviously, even minimal elevations can have significant impact.  

Renal: Approximately 1% to 5% of NSAID users may experience renal effects, though it is uncommon for nonprescription NSAIDs to cause acute renal failure.23 However, caution should be taken in individuals with decreased effective circulating volume, such as those with CHF, hepatic cirrhosis, chronic renal disease, or dehydration.1,18,21 In these individuals, renal perfusion is preserved by enhanced prostaglandin production. The inhibition of prostaglandins by NSAIDs can impair the adequacy of renal prostaglandin production, leading to vasoconstriction and, subsequently, a decline in renal blood flow and glomerular filtration rate. The FDA has identified populations with the following conditions and characteristics as being at-risk for NSAID-induced nephrotoxicity1,7,20:

* Volume depletion

* Underlying kidney disease

* Congestive heart failure

* Age >65 years

* Hypertension

* Diabetes mellitus with renal dysfunction

In healthy individuals, NSAIDs should not adversely affect renal function, but it is imperative that prior to an NSAID recommendation pharmacists identify at-risk individuals.  

Anemia: NSAID use may also exacerbate anemia, potentially due to fluid retention or gastrointestinal blood loss. Therefore, if patients are to receive long-term NSAID therapy or have an initial hemoglobin value <10 g/dL, periodic hemoglobin monitoring should be instigated.5 

Asthma Exacerbation: Jenkins et al concluded in a systematic review that aspirin-induced asthma affects approximately 21% of the adult population with asthma.1 In the review, almost all patients with aspirin-induced asthma displayed a cross-sensitivity to nonprescription doses of NSAIDs. Thus, individuals known to have aspirin-induced asthma should avoid all nonprescription NSAIDs. In patients who have asthma and who have not previously tried aspirin or other NSAIDs, acetaminophen should be the recommended agent. If anti-inflammatory action is necessary, these patients should consult a provider prior to self-care with NSAIDs to ensure that proper monitoring parameters and general care measures are followed.  

Conception, Pregnancy, and Lactation: Within the past few years, data have emerged that raise concern that NSAID use at the time of conception may increase the risk of miscarriage.1 Though further research is necessary to determine the validity of this, it may be prudent to advise women who wish to conceive in the immediate future to avoid self-care with NSAIDs, if reasonable. However, once a woman is in the first or second trimester of pregnancy, NSAIDs are regarded as relatively safe if the benefits of use outweigh the risks. NSAIDs should be avoided in the third trimester of pregnancy and during lactation due to the potential for premature closure of the fetal ductus and the potential adverse effects to the infant from NSAID-induced prostaglandin inhibition.1,5  

Interactions

Reports have demonstrated that a substantial percentage of individuals utilize low-dose aspirin for cardioprotection in addition to a nonprescription NSAID and a selective COX-2 inhibitor.1 Concurrent use of two NSAIDs, prescription or nonprescription, should be avoided due to the increased risk of upper gastrointestinal bleeding.1 There is also research that has demonstrated that use of ibuprofen at the 400-mg dose may limit the cardioprotective effects of immediate-release, low-dose aspirin, particularly in patients with established cardiovascular disease.1 Further research is necessary, including studies evaluating the effect of concurrent ibuprofen and enteric-coated aspirin. Currently, the FDA recommends that ibuprofen be taken more than 8 hours prior to or at least 30 minutes after the administration of immediate-release, low-dose aspirin.24

As noted previously, antihypertensive therapy presents a drug-drug interaction with the use of NSAIDs. NSAIDs may inhibit the actions of diuretic therapy, thus worsening volume overload in susceptible individuals, such as those with congestive heart failure.18  In patients with renal hypoperfusion or renal impairment, particularly the elderly, concurrent use of NSAIDs and ACE inhibitors will interfere with physiologic mechanisms that serve to protect the kidneys. Thus, NSAIDs should ideally not be used in patients taking prostaglandin-mediated antihypertensive therapy. However, when quality-of-life issues necessitate the combination of antihypertensive and chronic NSAID therapies, the antihypertensive agents should be adjusted accordingly and monitoring parameters instigated at regular intervals.5

The risk of gastrointestinal bleeding with NSAIDs is increased if concurrently taken with corticosteroids (prolonged use), anticoagulants, platelet inhibitors, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, or certain herbals (e.g., garlic, ginger, ginkgo).5

Concomitant use of alcohol and tobacco may also increase the gastrointestinal effects of NSAIDs.5 The FDA has mandated that all packaging for nonprescription NSAIDs advise individuals not to consume more than three alcoholic beverages per day when using these agents. Those who choose to use alcohol or tobacco with NSAIDs should be monitored closely for signs or symptoms of bleeding.

Patients who are susceptible to seizures and are taking a quinolone antibiotic for an extended period of time should not use NSAIDs, as this combination may lower the seizure threshold.5 NSAIDs may also interfere with lithium and methotrexate excretion, causing the potential for toxicity. Lithium concentrations increase over 5 to 10 days after initiation of an NSAID and return to normal within 7 days of discontinuation of the NSAID. NSAID interference with methotrexate is not seen at lower doses of methotrexate, such as those used to treat rheumatoid arthritis, but may be seen at higher doses, such as those used for treatment of psoriasis or malignant disease.5,25 

Conclusion

Referring to the case presented at the beginning of this article, it is obvious that this individual is inappropriately self-dosing his analgesic therapy and possibly self-treating to avoid additional costs associated with a medical visit. The excessive amounts of ibuprofen and naproxen used, as well as the concurrent therapy with two NSAIDs, increase his risk for gastrointestinal bleeding. The presenting symptoms of stomach pains and blood in his stool are most likely attributed to his misuse of nonprescription analgesic therapy. Though this is an extreme  but real case of self-care abuse, nonprescription NSAIDs are not benign medications, even at low doses. Patients who are elderly and those with existing renal disease, cardiovascular disease, or aspirin-sensitive asthma are at most risk for severe NSAID-induced complications. Because of the widespread use of these medications and an underappreciated risk, pharmacists should be at the forefront for assessing patients for appropriateness of use, as well as for providing counseling on proper use, adverse effects, and drug interactions.  

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