Common Adverse Events and Interactions with OTC Pain Medications

US Pharm. 2008;33(5):44-56.

Approximately 36 million Americans use OTC pain medications daily.¹ In recent years, drug stores, supermarkets, and mass merchandisers have sold more than $2 billion in OTC pain medications.² It is safe to say that OTC analgesics are widely used by people of all ages. In a recent study, Wilcox et al found that although the public uses OTC analgesics widely, they are generally unaware of the potential for adverse effects. Consumers take these medications inappropriately and even potentially dangerously on a regular basis.¹

Among the options for OTC pain medications or analgesics are acetaminophen (e.g., Tylenol) and nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs include aspirin, ibuprofen (e.g., Advil, Motrin), ketoprofen (e.g., Orudis KT), naproxen (e.g., Aleve), and other, less frequently used salicylates marketed for back pain (e.g., salicylate, trisalicylate).^2,3 Many combination products containing both acetaminophen and aspirin are also available (e.g., Excedrin, Vanquish). ³

The FDA warns consumers that all OTC pain relievers should be taken carefully to avoid serious problems that may occur with improper usage.⁴ Pharmacists can be instrumental in assisting patients with using OTC medications safely and effectively. This article will help pharmacists become better equipped to do this by discussing commonly seen adverse events and interactions in OTC pain medications, with focus on acetaminophen and NSAIDs as a class (TABLE 1 ).

ACETAMINOPHEN
Acetaminophen is generally considered a safe and effective pain reliever.⁴ It is one of the most commonly used drugs and can be found in over 200 OTC products. ⁵ While it is very safe when taken at normal doses, the danger of this drug lies in exceeding the recommended dose, either acutely or chronically. Acetaminophen has been identified as the most common cause of acute liver failure; unintentional overdose accounts for many acute liver failure cases. ⁵

There are many reasons that a patient could overdose unintentionally. First of all, acetaminophen is found in a wide variety of products--single entity, combinations, multiple formulations--available both OTC and by prescription. Because these products are sometimes not recognized by consumers as containing acetaminophen, it is quite easy to accidentally combine products, exceeding the recommended dose. Pharmacy labeling may not clearly indicate that acetaminophen is an ingredient in the prescription pharmaceutical product, using either trade names or the abbreviation APAP. Secondly, there is a lack of awareness among the general public regarding the potential adverse effects of either exceeding the recommended dose ("twice as much must work twice as well") or taking two products containing acetaminophen simultaneously.⁶ It is clear that unintentional overdose could easily happen to an uninformed consumer. Children are at a great risk of overdose, due to unknowingly being given a combination of acetaminophen-containing products and also because the giver may have difficulty in determining and measuring the correct dose (concentrated products may be mistaken for less concentrated products, i.e., infant drops versus suspension).⁵

Mechanism of Action and Metabolism
Possessing both analgesic and antipyretic activity similar to that of aspirin, acetaminophen has no peripheral anti-inflammatory or antiplatelet effects. Acetaminophen is believed to act primarily on the central nervous system, increasing the pain threshold by inhibiting cyclooxygenase (COX)-1 and COX-2, enzymes involved in the synthesis of prostaglandins. Acetaminophen has no peripheral COX effects and therefore is ineffective in reducing inflammation in the tissues.⁷ The lack of inhibition of COX-1 specifically in the tissues explains the fact that acetaminophen causes no gastrointestinal (GI) adverse effects.

Acetaminophen is largely metabolized by glucuronidation and sulfate conjugation in the liver (85%-90%). The rest is oxidated by CYP450 isoenzymes to N -acetyl-para-benzoquinoneimine (NAPQI) in the liver and also in the kidney to a lesser degree. NAPQI is normally excreted by the body in the urine after being conjugated by glutathione from the liver. When this process is interrupted and excess NAPQI is present, both the liver and the kidneys are adversely affected. It is this toxic metabolite that leads to acetaminophen's harmful effects, by binding to the tissues and leading to cell necrosis.⁷

Adverse Reactions
Hepatotoxicity arises from depletion of glutathione reserves in the liver, due to chronic high doses of acetaminophen, chronic alcohol consumption, AIDS, or poor nutrition. With no glutathione, the liver has no defense against the toxic NAPQI that is present after CYP metabolism of acetaminophen. Drug-induced hepatotoxicity is characterized by hepatic necrosis, jaundice, bleeding, and encephalopathy. Dose-dependent hepatotoxicity is seen in acute acetaminophen overdose, but even moderately excessive doses can produce hepatotoxicity if taken chronically. Children appear to be at somewhat less risk for developing hepatotoxicity due to an age-related difference in the way the drug is metabolized.⁷ Signs of liver disease include jaundice of the skin and eyes, dark urine, light-colored stools, nausea, vomiting, and loss of appetite.⁴ Liver damage may be blunted by the administration of N -acetylcysteine (e.g., Mucomyst) or methionine, which reduce the binding of NAPQI to tissues. These drugs do not, however, prevent renal toxicity.⁷

Acute renal failure may occur in as many as 30% of patients who first develop liver dysfunction. It is also dose dependent. Metabolites can accumulate at all doses in patients with renal insufficiency. Toxic metabolites other than NAPQI may also play a role in acetaminophen-induced acute renal toxicity. Alcohol seems to increase the risk of renal complications. In patients with normal renal function who take analgesics including acetaminophen, chronic analgesic nephropathy can occur. Chronic analgesic nephropathy is damaging to the kidney due to either reactive metabolites or inhibition of renal COX. The effects of this condition are twofold--interstitial nephritis and papillary necrosis. The use of acetaminophen in combination with salicylates for prolonged periods of time is not recommended, as this can lead to analgesic nephropathy.⁷

Other adverse effects of acetaminophen use include skin reactions. Hypersensitivity reactions are rare, but may be manifested by urticaria, erythema, generalized pruritus, rash, and fever. Anaphylaxis has been reported very rarely with the drug. Drug-induced rebound headache may also occur with acetaminophen overuse, in which frequency of use is probably more important than the dose used.⁷

Drug Interactions
There are many drug interactions associated with acetaminophen. Most notable is the combination of multiple products containing acetaminophen, as previously discussed. The second most notable is concurrent use of acetaminophen and alcohol. Chronic ethanol ingestion can lead to hepatotoxicity even at normal acetaminophen dosages. This drug interaction is mediated by the induction of CYP2E1, which is the main CYP450 enzyme involved in acetaminophen metabolism, along with CYP1A2.⁷ Chronic heavy drinkers should be advised to avoid or limit use of acetaminophen.⁵ Some pharmacists recommend decreasing the maximum daily dose from 4 g/day for normal adults to 2 g/day for patients with alcoholism. Acetaminophen should be avoided during acute periods of heavy ethanol consumption. However, it has been reported that cases of alcohol-associated acetaminophen toxicity are most likely attributed to intentional overdose.⁵

Drugs that induce CYP2E1 and CYP1A2 may increase the risk of acetaminophen-induced hepatotoxicity by leading to the generation of more NAPQI than normal. These drugs include carbamazepine, oxcarbazepine, barbiturates, phenytoin, fosphenytoin, isoniazid, rifampin, and rifabutin.⁷ Other evidence, however, reports that these interactions may not be clinically significant.⁵ Tobacco is an inducer of CYP1A2 and has been found frequently in patients admitted with acetaminophen toxicity. Tobacco smoking may be an independent risk factor for severe hepatotoxicity, acute liver failure, and death following overdose of acetaminophen.⁷

NSAIDs
Aspirin is the original universal pain reliever and is still a popular drug today.² Due to certain side effects (i.e., bleeding and GI problems), its primary use is for cardiovascular prophylaxis.² In myocardial infarction, it saves lives and is considered first-line treatment. Other NSAIDs are more likely to be chosen when an OTC pain reliever is being sought.

Besides aspirin, other NSAIDs available OTC include ibuprofen, naproxen, and ketoprofen (TABLE 1). Advil (ibuprofen) is the best-selling brand among the OTC pain relievers, with sales of nearly $280 million per year.² NSAIDs are used to treat inflammation, pain, and fever.

Mechanism of Action and Metabolism
NSAIDs work by inhibiting the COX-1 and COX-2 enzymes, effectively blocking the conversion of arachidonic acid to prostaglandin G₂, the first of many steps in the synthesis of prostaglandins and thromboxanes. Prostaglandins and thromboxanes are involved in rapid physiologic responses, most notably inflammation. It is the inhibition of COX enzymes that leads to both the pharmacologic and adverse effects of NSAIDs.⁸

COX-2 is thought to be most important in the inflammatory response. It is found in the brain, kidneys, bones, reproductive organs, and some cancers. COX-1 can be found in almost all tissues and is responsible for maintenance of normal renal function, gastric mucosal integrity, and hemostasis. It is commonly referred to as the "housekeeping" enzyme.⁸

The anti-inflammatory activity of NSAIDs is due to the decreased synthesis of prostaglandins via COX-1 and COX-2 inhibition. Although COX-2 is more closely associated with inflammation, COX-1 is also expressed at some sites of inflammation, including the joints of patients with rheumatoid or osteoarthritis. The NSAIDs available OTC are slightly more selective for COX-1 than COX-2.⁸ COX-2 selective NSAIDs are currently available by prescription only (i.e., celecoxib [Celebrex], meloxicam [Mobic]) and may provide some benefit over the nonselective NSAIDs by causing fewer GI side effects.⁹

NSAIDs also have an indirect analgesic effect by blocking the synthesis of specific prostaglandins responsible for sensitizing pain receptors. They do not directly affect the pain threshold. The antipyretic effect of NSAIDs is due to their inhibition of prostaglandins in and near the hypothalamus, promoting a return to a normal body temperature set point. NSAIDs may therefore mask fever if used in high or chronic doses.⁸

NSAIDs are metabolized by the liver, either by the CYP450 system (ibuprofen and naproxen) or by glucuronic acid conjugation (ketoprofen). NSAIDs have been infrequently linked to hepatotoxicity such as hepatitis or jaundice. Patients with elevated hepatic enzymes before or during therapy should be monitored closely.⁸

Adverse Reactions
The inhibition of COX-1 leads to the GI problems caused by NSAIDs. This is compounded by the direct irritant action on the stomach wall, as well as by the increased bleeding time due to changes in platelet aggregation. GI adverse reactions are the most frequently reported reaction to NSAIDs. These include anorexia, nausea, vomiting, epigastric pain, dyspepsia, constipation, diarrhea, gastritis, dark tarry stools, and flatulence. Severe GI effects include gastric ulceration with or without bleeding, peptic ulcer disease, or GI perforation. Severe reactions may occur without early GI manifestations. Patients who have a history of peptic ulcer disease, GI bleed, smoking, alcohol usage, or who have poor general health, are elderly, or take anticoagulants, corticosteroids, or chronic NSAIDs are at greater risk for severe GI events.⁸ TABLE 2 contains a summary of risk factors for adverse upper GI events.¹⁰ Use of NSAIDs along with low-dose aspirin also places patients at risk.⁶ Rarely, these GI effects extend to the esophagus, especially if the medication is taken at night and without water.⁸

NSAIDs may cause platelet dysfunction, leading to decreased levels of platelet thromboxane A₂ and an increase in bleeding time. Aspirin is used to prevent platelet aggregation by binding COX-1 for the life of the enzyme. Other NSAIDs do not bind irreversibly to COX-1. Because this is a competitive inhibition, aspirin's effects may be thwarted if another NSAID is taken first. Because it is a reversible inhibition, aspirin may still be effective if taken long enough after another NSAID for the platelet effect to reverse.⁸ If aspirin is being taken for cardioprotection, it should be taken 30 minutes before another NSAID. Of course, caution should be exercised to avoid GI problems in these patients.

COX-1 and COX-2 are important for maintaining proper renal function. Prostaglandins produced by both COX isoenzymes work in the kidney to regulate sodium and water reabsorption and hemodynamics. Therefore, NSAIDs may interfere with renal function in instances where renal blood flow is dependent upon prostaglandin synthesis. Significant decreases in renal blood flow may lead to acute renal failure. Changes in the reabsorption of sodium and water may become significant in certain individuals, resulting in increased blood pressure. Fluid retention and edema may occur as a result of sodium and water reabsorption. Exacerbation of congestive heart failure or hypertension may occur in patients taking NSAIDs. There may be an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke.⁸ Risk factors for NSAID-related renal toxicity include volume depletion, underlying kidney disease, congestive heart failure, age over 65 years, hypertension, and diabetes.⁶

NSAIDs have also been reported to cause rash, including Stevens-Johnson syndrome. Asthmatics may suffer bronchospasm, dyspnea, and wheezing with NSAID therapy, due to excessive production of leukotrienes. Aseptic meningitis has been rarely reported with NSAID use, most commonly ibuprofen. NSAIDs may cause exacerbation of anemia due to fluid retention, GI blood loss, or an ill-understood effect on erythrogenesis. Overuse of NSAIDs may produce a drug-induced rebound headache accompanied by dependence on symptomatic medication, tolerance to the drug, and even symptoms of withdrawal.⁸

Drug Interactions
The potential for adverse GI effects with NSAIDs may be increased by concomitant use of many other drugs, including other NSAIDs, ethanol, tobacco, ketorolac, corticosteroids, bisphosphonates, and cholinesterase inhibitors. Because of possible GI bleeding, platelet inhibition, and prolonged bleeding time, caution should be exercised when taking NSAIDs with salicylates, selective serotonin reuptake inhibitors (SSRIs), and platelet inhibitors or anticoagulants.⁸

NSAIDs have been shown to reduce the effectiveness of antihypertensive medications. This applies to diuretics, beta-blockers, ACE inhibitors, vasodilators, central alpha-2 agonists, peripheral alpha-1 blockers, and angiotensin receptor blockers. Doses of antihypertensive medications may need to be adjusted in patients who regularly take NSAIDs. Volume depletion may occur with use of diuretics, which in combination with the inhibition of prostaglandin synthesis with NSAIDs may lead to renal failure from insufficient renal perfusion.⁸

Concurrent use of NSAIDs and other potentially nephrotoxic agents may lead to additive nephrotoxicity. These may include aminoglycosides, amphotericin B, systemic bacitracin, cisplatin, gold compounds, ganciclovir, pamidronate, pentamidine, tacrolimus, foscarnet, parenteral vancomycin, and zoledronic acid, as well as tenofovir, cidofovir, adefovir, and entacavir. Cyclosporine serum concentrations may be increased when an NSAID is also taken, potentiating the renal dysfunction associated with the drug. Elderly patients are at a greater risk of adverse renal events due to age-related decreases in renal function.⁸

CONCLUSION
OTC pain medications should be used at the lowest effective dose for the shortest duration possible to minimize the potential risk for an adverse event. Patients taking acetaminophen should not exceed the recommended maximum daily dose, while patients taking NSAIDs should not exceed the recommended single or daily dose.⁶ Doses given to children and infants should be very carefully measured, with the dosing device that comes packaged with the drug product. Labels for prescription medications containing OTC ingredients should be clear and should not contain abbreviations such as APAP.⁵

Patient and consumer education is also essential in preventing damage caused by these seemingly harmless medications. The pharmacist has a great opportunity to intervene. Encourage patients who take prescription medications containing acetaminophen or an NSAID to pay special attention to the ingredients on any OTC medication labels they are also using to reduce the incidence of accidental analgesic overdosing. Provide educational materials to patients so that they may learn to recognize the generic names of these medications. Warn consumers of the risks of misusing OTC pain relievers. While these drugs are safe and effective when taken at recommended doses, they may be quite harmful, even fatal, when taken inappropriately. Pharmacists can make a critically important contribution to the safety of patients taking acetaminophen- and NSAID-containing products.⁷ It is our duty to help patients use OTC medications safely.

REFERENCES
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