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OTC analgesics and drug interactions: clinical implications
© Fendrick et al; licensee BioMed Central Ltd. 2008
Received: 09 November 2007
Accepted: 07 February 2008
Published: 07 February 2008
The risk of drug interactions with concurrent use of multiple medications is a clinically relevant issue. Many patients are unaware that over-the-counter (OTC) analgesics can cause potentially serious adverse effects when used in combination with other common medications such as anticoagulants, corticosteroids, or antihypertensive agents. Of particular significance is the increased risk of upper abdominal gastrointestinal adverse events in patients who take traditional nonsteroidal anti-inflammatory drugs (NSAIDs). This risk is dose dependent and further increased in patients who take more than one NSAID or use NSAIDs in combination with certain other medications. Some NSAIDs may also mitigate the antiplatelet benefits of aspirin and may increase blood pressure in patients with hypertension. Clinicians should be aware of potential drug interactions with OTC analgesics when prescribing new medications. Additionally, patients should be properly counseled on the appropriate and safe use of OTC analgesics.
A survey of medication use patterns in the United States has found that more than 80% of American adults used at least one over-the-counter (OTC) or prescription drug each week, and that 25% used at least 5 . The OTC analgesics acetaminophen, ibuprofen, and aspirin are among the most frequently utilized medications, used by approximately 17% to 23% of the population each week. Chronic OTC analgesic use is most common in the elderly, many of whom take nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for relief of pain. In addition, a recent survey reported that approximately 50% of American adults classified as having high cardiovascular (CV) risk status take low-dose aspirin for CV prophylaxis [1–3].
Because of the widespread availability and perceived safety of OTC analgesics, self-medication with these agents has become commonplace. Many patients are unaware of the potential for toxicity and adverse drug interactions associated with the long-term and inappropriate use of OTC analgesics. They may use OTC analgesics in higher-than-recommended doses or in combinations that magnify the risk of adverse interactions. Additionally, patients may not be aware that common cough, cold, or flu medications can contain OTC analgesics. Although OTC analgesics are associated with adverse effects in only a small percentage of people, the widespread use of these drugs makes even a small increase in population risk a clinically relevant issue . Physicians can help patients avoid possible drug-drug interactions with commonly used OTC analgesics by providing counseling on the proper use of these agents.
Currently available OTC oral analgesics and mechanisms of action
There are currently 4 OTC oral analgesics available in the United States: acetaminophen, aspirin, ibuprofen, and naproxen . When taken as recommended, these OTC analgesics present relatively safe, effective, and economical treatments for mild to moderate pain, inflammation, and fever. Nevertheless, as a result of their accessibility and presumed safety, OTC analgesics are among the most commonly ingested drugs in overdoses .
Acetaminophen is generally considered to exert its analgesic effects through the inhibition of prostaglandin (PG) synthesis in the central nervous system , although the exact mechanism is not clearly defined. Several recent studies [7, 8] have suggested alternative pathways, including peripheral elevation of the pain threshold. Aspirin and other NSAIDs inhibit the cyclooxygenase (COX) enzyme, thereby decreasing synthesis of PGs and related compounds that contribute to the inflammatory response and mediate a variety of cellular functions [9, 10]. Traditional NSAIDs are nonselective for the 2 subtypes of the COX enzyme, although aspirin is 170-fold more potent in inhibiting COX-1 than COX-2 . Whereas COX-1 inhibition by traditional NSAIDs is reversible, aspirin completely inactivates and irreversibly inhibits platelet COX-1, thus preventing formation of thromboxane A2[2, 9].
Potential drug interactions with OTC analgesics
Potential drug interactions with OTC analgesics[5,42,43]
Aspirin and NSAIDs or multiple NSAIDs
Increased risk of serious GI complications. Risk increases with increased dose and number of agents
Avoid concurrent use of more than one NSAID, if possible. Consider adding gastroprotective agents
Anticoagulants and NSAIDs
Increased risk of bleeding (especially GI) and increased oral warfarin activity
Avoid concurrent use of NSAID; monitor prothrombin time and occult blood in urine and stool
Corticosteroids and NSAIDs
Increased GI side effects, including ulceration and hemorrhage
Avoid concurrent use of NSAID and consider adding a gastroprotective agent
SSRIs and NSAIDs
Increased risk of GI bleeding
Avoid concurrent use of NSAID
Aspirin and ibuprofen or naproxen
Reduced antiplatelet effects of aspirin
Not seen with other NSAIDs or acetaminophen
Antihypertensive agents and NSAIDs
Use of NSAIDs may increase blood pressure
Monitor blood pressure and cardiac function
Antidiabetic agents (eg, sulfonylureas) and aspirin
Increased hypoglycemic effect
Avoid concurrent use and monitor blood glucose concentration
Lithium and NSAIDs
Increased steady-state lithium concentration and lithium toxicity
Monitor lithium concentrations. Interactions are less likely with aspirin than with naproxen or ibuprofen
Methotrexate and NSAIDs
Reduced renal clearance. Increased plasma methotrexate concentration
Avoid NSAIDs with high-dose methotrexate
Increased GI bleeding risk
Inhibition of COX by aspirin and other NSAIDs interferes with the production of protective mucosal PGs . This mechanism likely explains the increased incidence of gastric ulcers and upper GI bleeding with use of NSAIDs. Listed below are several risk factors that increase the likelihood of developing GI toxicity with NSAIDs use [11–13]:
• Advanced age
• History of GI events
• Increased NSAID dose or multiple NSAID use
• Concomitant aspirin use.
Elderly patients are at greater risk of developing GI complications and often have comorbidities that require analgesic treatment . Thus, careful monitoring of the amount of OTC and prescription NSAID consumption is imperative in the management of elderly patients. To minimize GI adverse events, proton-pump inhibitors (PPIs) or other gastroprotective agents may be useful for patients who require NSAIDs for anti-inflammatory therapy and are at risk for increased GI events [14, 15].
Adverse GI effects are further compounded by the use of more than one agent and with higher NSAID doses [11, 13, 16]. Concomitant use of aspirin and traditional NSAIDs can double the risk of GI toxicity, as reported in a study of low-dose aspirin used for CV prophylaxis . The standardized incidence rate of upper GI bleeding was 2.6 (95% confidence interval [CI]: 1.8–3.5) for patients using low-dose aspirin alone and 5.6 (95% CI: 4.4–7.0) for those using low-dose aspirin in addition to traditional NSAIDs. Gutthann and colleagues  reported much higher incidence of upper GI bleeding or perforation in patients who used multiple NSAIDs (adjusted OR = 9.0 [95% CI: 5.9–13.6]).
Although there is little inherent risk of GI events with anticoagulant use, several studies have shown that concomitant treatment with aspirin and other NSAIDs can increase the risk of GI hemorrhage and perforation [12, 13]. This may be linked to the impairment of platelet aggregation induced by aspirin and nonselective NSAIDs . A study by Shorr and colleagues  reported a nearly 13-fold increase (95% CI: 6.3–25.7) in risk of developing hemorrhagic peptic ulcer disease with concurrent use of NSAIDs and anticoagulants in patients aged 65 years and older. A similar study conducted in patients aged 25 to 80 years reported an adjusted relative risk (RR) of 6.4 (95% CI: 2.8–14.6) for developing upper GI bleeding and perforation in patients using an NSAID and an anticoagulant, compared with those who had not received either drug .
Corticosteroids may cause decreased gastric mucus production and delayed healing of NSAID-induced erosions . The use of corticosteroids in patients not receiving NSAIDs is linked to a modest increase in GI events (OR range, 1.1 – 2.3) [11, 22]. Nevertheless, there is wide reporting in the literature of a dramatic increase in the risk of adverse GI effects, including ulceration and hemorrhage, with concomitant current use of corticosteroids and NSAIDs (OR range, 2.2 – 14.6, in various studies) [11, 13, 22]. Piper and colleagues (1991) demonstrated that patients receiving corticosteroids (eg, cortisone 25 mg, hydrocortisone 20 mg, prednisolone 5 mg, prednisone 5 mg) in combination with NSAIDs had a 15 times greater risk for peptic ulcer disease than that of nonusers of either drug. Thus, although corticosteroids may not inherently increase the risk of GI toxicity, they exacerbate the risk posed by NSAIDs by delaying the healing of NSAID-induced ulcers.
Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of upper GI bleeding [23, 24]. Serotonin is essential in initiating the hemostatic response of platelets to vascular injury . By blocking platelet uptake of serotonin, SSRIs may attenuate their function. Thus, SSRIs may impair hemostatic function and exacerbate underlying GI conditions when used concomitantly with drugs that cause GI ulceration and bleeding (eg, NSAIDs) . A recent case-control study reported a low risk of GI adverse events with use of SSRIs (OR = 1.30 [95% CI: 1.13–1.50], compared with nonuse of SSRIs or NSAIDs), but confirmed an increased risk with concomitant use of NSAIDs (OR = 4.19 [95% CI: 3.30–5.31], compared with nonuse of either drug) .
Acetaminophen may be an effective alternative to NSAIDs for patients who require an analgesic and who are on concomitant aspirin, anticoagulant, corticosteroid, or SSRI therapy. Patients should be educated on the risk factors for developing adverse GI events with use of NSAIDs and on appropriate ways to minimize further risks.
Interference with the antiplatelet effects of aspirin
Numerous studies have shown that ibuprofen interferes with the antiplatelet effects of aspirin [26, 28, 29]. Catella-Lawson and colleagues  evaluated whether the antiplatelet effects of aspirin were mitigated by the concurrent use of ibuprofen, diclofenac, rofecoxib, and acetaminophen. Ibuprofen, administered as a single 400 mg dose given before aspirin (81 mg) or as 3 400 mg doses after a single 81 mg dose of aspirin, blocked the irreversible inhibition of platelet aggregation by aspirin. In contrast, the concomitant administration of rofecoxib (25 mg once daily), diclofenac (75 mg twice daily), or acetaminophen (1000 mg once daily) – administered either before or after a dose of aspirin – did not affect the inhibition of platelet aggregation by aspirin. Another study reported an increased risk in recurrent acute myocardial infarction with prolonged use of ibuprofen and aspirin compared with use of aspirin alone (hazard ratio for duration of exposure for at least 60 days = 1.83 [0.76–4.42]) . Patients who take ibuprofen in addition to low-dose aspirin for CV prophylaxis should be mindful of the potential for drug interactions that may undermine the cardioprotective benefits of aspirin.
Recent studies on the effect of naproxen on platelet and vascular prostanoid inhibition have yielded inconclusive results [27, 30]. Unlike aspirin, naproxen inhibits prostacyclin synthesis, the clinical implication of which is currently unknown. Nonetheless, naproxen is commonly suggested as an alternative to ibuprofen in patients with established CV risk who take daily low-dose aspirin for CV prophylaxis . Other alternatives for analgesia for patients receiving long-term low-dose aspirin therapy include acetaminophen or other NSAIDs such as diclofenac, which do not preferentially inhibit COX-1. Because acetaminophen is a weak inhibitor of COX-1, it does not interfere with aspirin-mediated antiplatelet effects .
Other potential interactions and issues
By inhibiting prostaglandin synthesis, NSAIDs can induce sodium retention and vasoconstriction . Clinical studies have linked the use of NSAIDs to elevated blood pressure, particularly in patients with a history of hypertension who are already on antihypertensive medications [32–35]. In a meta-analysis of randomized trials studying the effect of NSAIDs on blood pressure, NSAIDs raised mean blood pressure by 5.0 mm Hg . Patients who were concomitantly using β-blockers experienced greater elevations in mean blood pressure (6.2 mm Hg) compared with those using either vasodilators or diuretics. Careful monitoring of blood pressure and cardiac function is therefore recommended for hypertensive patients when initiating NSAID therapy. The potential risk of CV events with use of NSAIDs has been studied extensively in recent years. In 2005, the US Food and Drug Administration issued a request that manufacturers of all nonaspirin NSAIDs, including COX-2 inhibitors, revise package inserts to include a black box warning highlighting the increased risk for CV events and GI bleeding with use of these drugs .
Other medications may have adverse interactions when taken in conjunction with OTC analgesics (Table 1). Aspirin, particularly in combination with anticoagulation therapy, has been shown to increase the risk of intracerebral hemorrhages (ICH) . Although ICH is an uncommon adverse effect of aspirin, the morbidity associated with this condition makes it a clinically relevant issue. Concomitant use of NSAIDs and antidiabetic agents, particularly sulfonylureas, may increase the risk of transient hypoglycemia . NSAIDs have also been shown to increase risk of lithium and methotrexate toxicity by increasing drug concentrations to unsafe levels [39–41]. Monitoring drug concentrations and adjusting dosages when necessary may reduce the likelihood of adverse drug interactions with use of OTC analgesics.
Approach to patient management
Clinicians' guide to anti-inflammatory therapy (reproduced from reference , with permission)
No or low NSAID gastrointestinal risk
NSAID gastrointestinal risk
No cardiovascular risk (without aspirin)
Nonselective NSAID (cost consideration)
COX-2 selective inhibitor or nonselective NSAID and proton-pump inhibitor
COX-2 selective inhibitor and proton-pump inhibitor for those with prior GI bleeding
Cardiovascular risk (with aspirin)
Proton-pump inhibitor irrespective of NSAID
Addition of proton-pump inhibitor if gastrointestinal risk of aspirin/NSAID combination warrants gastroprotection
Naproxen if CV risk outweighs GI risk
COX-2 selective inhibitor and proton-pump inhibitor for those with previous GI bleeding
A patient with established CV risk factors (taking aspirin for CV prophylaxis) who is at minimal risk of NSAID-induced GI complications may use naproxen or another NSAID without established aspirin interaction. A PPI may be added to this regimen should the combination of aspirin and NSAID warrant gastroprotection. Patients with established CV and GI risk factors should receive a PPI to be used in conjunction with NSAIDs. If the CV risk factors outweigh the GI risk factors, naproxen is recommended. As above, in a patient who has had previous GI bleeding, the clinician should suggest the use of a COX-2 selective inhibitor.
Additional recommendations include monitoring blood pressure and cardiac function in patients with hypertension. In diabetic patients receiving sulfonylureas and NSAIDs (including aspirin), routine checks for signals of increased hypoglycemia should be performed. All patients should be educated on potential drug interactions that may occur with OTC analgesics and prescription medications.
Because many patients self-medicate with OTC analgesics and are unaware of potentially dangerous drug interactions, proper counseling on the appropriate use of these agents can help minimize adverse effects and ensure positive clinical outcomes.
Funding for editorial assistance was provided by McNeil Consumer Healthcare, Fort Washington, Pennsylvania.
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