The nonopioid analgesics are the drugs of choice for treating mild to moderate pain. Among these, the NSAIDs are typically the most effective and are usually safe for short-term use. Although some clinicians regard the NSAIDs as generally less effective but safer than narcotic analgesics, this presumption is misleading, because both types of analgesics have a significant side- effect potential.The NSAIDs are effective for many types of acute ocular pain, especially when the pain is associ- ated with inflammation. Acetaminophen is also useful as an analgesic for mild to moderate pain but has no effect on inflammation.
Salicylates
Pharmacology
The salicylate aspirin (acetylsalicylic acid) is the oldest nonopioid analgesic. In addition to analgesic effects, the salicylates have important anti-inflammatory and antipyretic properties.Acting primarily in peripheral tissues, aspirin reduces pain by inhibiting synthesis of the prostaglandin E2 by irreversible acetylation and
inactivation of cyclooxygenase (see Figure 7-1). The pharmacologic properties of aspirin are predominantly analgesic at lower doses but assume anti-inflammatory effects at higher doses. Full anti-inflammatory effects, however, generally require doses of at least 3 to 4 g daily.
Although aspirin relieves pain primarily through its activity in peripheral tissues (e.g., cornea or conjunc- tiva), it is also believed to have some central activity by influencing the perception of pain in the hypothala- mus. The central mechanisms of action have not been elucidated, but it is clear that when used in thera- peutic doses, the salicylates generally produce no clini- cally significant changes in sensorium or mood. This central activity probably accounts for the analgesic efficacy of aspirin in pain states not associated with inflammation.
All nonnarcotic analgesics, including the salicylates, have a “ceiling effect,” that is, a dosage beyond which no further analgesia occurs. Because the salicylates and other nonnarcotic analgesics do not produce tolerance or phys- ical or psychological dependence, they are relatively safe and nonaddicting. PAIN CNS Opioids block perception of and emotional response to pain
Damaged Cell Membrane
Arachidonic Acid NSAIDs block generation of pain signal by inhibiting synthesis of PGE2 Cyclooxygenase Histamine and Bradykinin NOCICEPTOR NOCICEPTOR PGE2 CORNEA L SURFA CE TRAUMA
Figure 7-1 Sensitization of nociceptors by prostaglandins and other inflammatory mediators to produce pain and inflamma- tion in ocular tissues. Clinically useful analgesics act either in peripheral tissues by inhibiting prostaglandin production
or centrally by interrupting the pain signal and its emotional consequences. (CNS = central nervous system;
Clinical Uses
The salicylates are beneficial for pain associated with inflammation, but their use has now been generally supplanted by other NSAIDs, largely because of gastroin- testinal (GI) distress. Nevertheless, the salicylates are effective for treatment of mild to moderate pain and may produce analgesic effects comparable with those of weak narcotics such as propoxyphene hydrochloride. When used in combination with narcotics, the salicylates can be effective for severe pain accompanying acute ocular trauma or inflammation.
Aspirin is commercially available in numerous formula- tions (Table 7-1). It is compounded as a tablet, an enteric- coated tablet, a controlled-release tablet, and as a suppository. Enteric-coated aspirin, which decreases GI tract irritation, is recommended for chronic use but is rarely required for the treatment of acute ocular pain, which usually resolves over several days. Likewise, controlled-release aspirin, because of its relatively long onset of action, is not recommended for treatment of acute ocular pain.
Aspirin is often given in a buffered form.The addition of small amounts of antacids decreases GI irritation and increases the dissolution and absorption rate of the aspirin. Nonacetylated salicylates, including salsalate, sodium salicylate, choline salicylate, magnesium salicy- late, and various salicylate combinations, are usually more expensive but can be effective. Although these aspirin substitutes provide less anti-inflammatory effects than aspirin, they exhibit minimal antiplatelet properties and have fewer GI side effects. They can therefore be useful for patients who cannot tolerate aspirin or other NSAIDs. The adult dosage of aspirin is 325 to 650 mg every 4 hours (not to exceed 4 g/day) as required for treatment of mild to moderate pain. Patients should be advised to take aspirin with food or shortly after meals to decrease GI upset. It should be taken with a full glass of water to reduce the risk of the medication lodging in the esopha- gus.Aspirin products that have a strong vinegar-like odor should be avoided.
Side Effects
GI disturbances are the most common adverse effects observed with therapeutic doses of salicylates. However, the short-term (less than 1 week) use of these agents does not usually cause any significant consequences.
Prostaglandins inhibit gastric acid secretion and have a protective effect on the mucosal lining. Aspirin-induced inhibition of prostaglandin synthesis results in increased gastric acid secretion and a more vulnerable gastric mucosa. As a result dyspepsia, gastric irritation, and GI bleeding can occur. Uncoated aspirin can also injure the stomach through a direct effect on the gastric mucosa. Enteric-coated aspirin or buffered preparations may help to minimize this problem. In addition, misoprostol, a prostaglandin analogue, can help to suppress the GI toxi- city associated with NSAIDs and should be considered for patients who require anti-inflammatory medication but have a history of duodenal ulcer or gastritis. Combination products are frequently less expensive and can often enhance patient compliance when compared with two separate drugs. Arthrotec incorporates misoprostol and diclofenac in one tablet.
All NSAIDs interfere with platelet aggregation, and because aspirin inactivates cyclooxygenase irreversibly, its effect is to prolong bleeding time (12 to 15 days).The formation of a gastric ulcer or erosion with profuse bleed- ing is a potentially serious problem with aspirin and other NSAIDs. Evidence indicates that choline–magnesium salicylate (Trilisate) does not inhibit platelet function and may therefore be indicated in some patients.
Aspirin hypersensitivity is also a potential concern and can occur in two ways: (1) a respiratory reaction, which is more profound in patients with rhinitis, asthma, or nasal polyps, or (2) a typical type I hypersensitivity reaction, including urticaria, wheals, angioedema, itching, rash, bronchospasm, laryngeal edema, hypotension, shock, or syncope. This latter response generally occurs within 1 hour of aspirin ingestion. Such aspirin intolerance may manifest itself in 4% to 19% of patients with asthma and may approach 40% of steroid-dependent asthmatics.
Table 7-1
Commonly Used Aspirin Products
Trade Name Formulation Dosage Unit (mg)
Aspirin (generic) Tablet 325
Genuine Bayer Tablet 325
Empirin Tablet 325
Bayer Extra Strength Tablet 500
Ecotrin Enteric-coated tablet 325
Ecotrin Maximum Strength Enteric-coated tablet 500
Aspirin (generic) Suppository 120, 200, 300, 600
Buffered aspirin (generic) Buffered tablet 325
Ascriptin A/D Coated, buffered tablet 325
Bufferin Coated, buffered tablet 325
Patients who are sensitive to aspirin should not be given any other NSAID because of possible cross-sensitivity reactions. Aspirin cross-sensitivity, however, does not appear to occur with the nonacetylated salicylates such as sodium salicylate or choline salicylate. As mentioned previously, aspirin hypersensitivity is more prevalent in patients with asthma, rhinitis, or nasal polyposis. This syndrome has been termed the “aspirin triad.”
CNS effects are infrequent yet possible, including confusion in some elderly patients, especially those over age 70 years. Headache, tinnitus, dizziness, and deafness may occur. In addition, aspirin can cause the retention of sodium and water and may reduce renal function, thus inducing acute systemic hypertension or exacerbating congestive heart failure. The effects of aspirin and other NSAIDs on blood pressure seem to be more evident among susceptible patients, such as those with preexist- ing hypertension. Aspirin also binds tightly to plasma proteins, which can displace other drugs from protein- binding sites, thereby increasing the pharmacologic effects related to the unbound drug. Patients on anticoag- ulant or oral hypoglycemic therapy, for example, must be monitored closely.
Use of aspirin during an antecedent viral infection, such as influenza or chickenpox, has been associated with Reye’s syndrome in a small but significant number of children and teenagers. Reye’s syndrome is a potentially fatal disease of unknown etiology characterized by vomit- ing, lethargy, fatty liver degeneration, encephalopathy, and variable hypoglycemia. Given effective alternatives such as acetaminophen, use of aspirin as an antipyretic and analgesic in children should be avoided.
Contraindications
The most important contraindications to salicylate therapy are listed in Box 7-1. As a general rule, when aspirin is contraindicated or is not well tolerated, acetaminophen
or a nonacetylated salicylate may be effective as an alter- native analgesic while minimizing the risk of side effects. Salicylates are contraindicated in patients with upper GI disease or a history of adult-onset asthma.They should also be avoided in patients with bleeding disorders such as hemophilia, those taking anticoagulants such as warfarin or heparin, and in individuals who consume more than three alcoholic beverages per day. Because aspirin or aspirin-containing products may lead to prolonged bleeding, it is prudent to limit or to avoid their use in patients who have had recent intraocular surgery or surgery of the eyelids. Likewise, aspirin should be avoided for treatment of pain associated with hyphema, because the incidence of rebleeding can be considerably increased.Aspirin is also contraindicated in patients who are sensitive to aspirin, nonsalicylate NSAIDs, or tartrazine (FDC yellow dye no. 5).
Aspirin ingestion during pregnancy can produce adverse effects in the mother, including anemia, prolonged gestation, and prolonged labor. During the later stages of pregnancy, aspirin can produce adverse effects in the fetus, including low birth weight, increased incidence of intracranial hemorrhage in premature infants, and even neonatal death. Because salicylates may be teratogenic, they should be avoided during pregnancy, especially in the third trimester. Salicylate use during breast-feeding may be safe; however, the drug is excreted into breast milk in low concentrations.
Nonsalicylate Nonsteroidal Anti-Inflammatory Drugs
The analgesic efficacy and safety profiles of the nonsalicy- late NSAIDs make them appropriate alternatives to aspirin for treatment of mild to moderate pain. Most NSAIDs are used primarily for their anti-inflammatory effects, but they are also effective analgesics that relieve pain associated with a variety of ocular conditions. The nonsalicylate NSAIDs consist of the propionic acid deriv- atives, cyclooxygenase-2 (COX-2) inhibitors, and several other less commonly used agents (Table 7-2).
Pharmacology
Like the salicylates, the nonsalicylate NSAIDs produce analgesic effects primarily by inhibiting cyclooxygenase in injured or inflamed tissues and thus reduce or elimi- nate production of the sensitizers for peripheral nocicep- tors (see Figure 7-1). In the CNS a less well-understood effect occurs whereby the recognition of pain is dimin- ished.The analgesic activity of the nonsalicylate NSAIDs, like the salicylates, is characterized by a ceiling effect, and repeated or chronic use causes neither drug tolerance nor addiction.
The largest class of NSAIDs with both anti-inflammatory and analgesic uses is the propionic acid derivatives (see Table 7-2). These drugs are metabolized in the liver and excreted in the urine. The analgesic effects among
Box 7-1 Contraindications to Aspirin and Nonsalicylate NSAIDs
Active upper gastrointestinal disease (peptic ulcers, hiatal hernia, dyspepsia, esophagitis)
History of heavy alcohol use (>3 alcoholic beverages daily)
History of bronchial asthma, nasal polyps, or aspirin hypersensitivity
Bleeding disorders, anticoagulant therapy, or vitamin K deficiency
Pre-/postop cataract or other invasive surgery Chronic renal or hepatic disease
Hypertension or congestive heart failure Pregnancy, especially third trimester/lactation Children or teenagers with flu-like (viral) symptoms
these drugs are approximately equivalent, but systemic absorption to achieve peak plasma levels varies with each agent. Naproxen (Anaprox) was developed specifically to facilitate absorption to reach a peak plasma level rapidly. Although studies that evaluate analgesic efficacy in painful ocular conditions are lacking, the results of other studies may be helpful to indicate the relative usefulness of various NSAIDs for treatment of ophthalmic pain. Table 7-3 summarizes the comparative analgesic efficacy of the commonly used NSAIDs relative to aspirin. The propionic acid derivatives are superior to aspirin in anal- gesic efficacy and appear to have a lower incidence and severity of side effects. In dental surgery patients, both ibuprofen and ketoprofen are more effective than 650 mg aspirin, and 100 mg ketoprofen is significantly more effective than 400 mg ibuprofen.
Clinical Uses
Variability in patient response to the NSAIDs in terms of efficacy and toxicity may be related to differences in binding affinity with cyclooxygenase in various tissues. Consequently, no definitive guidelines can be given in selecting the most appropriate NSAID for a given patient. The choice should be based on clinical experience, patient convenience or preference, history of favorable analgesic use, side effects, and cost. The primary indica- tions include painful conditions associated with inflam- mation, including postoperative and posttraumatic pain. The most effective analgesics tend to be those with a rapid onset of action, so that analgesia is achieved for the time corresponding to the acute phase of pain.
Although the NSAIDs are most useful for relief of mild to moderate pain, their analgesic effects are
Table 7-2
Commonly Used Nonsalicylate NSAIDs
Adult Analgesic
Classification Trade Name Generic Name Formulation Dosage (mg)
Propionic acids Motrin, Advil, Nuprin Ibuprofen 50-, 100-, 200–300- to 200–400 q4 h
400-, 600-, 800-mg tablets; 100-mg/5-ml suspension
Naprosyn Naproxen 250-, 375-, 500-mg 500 initial dose followed by
tablets; 125-mg/5-ml 250 q6–8 h or 500 q12 h
suspension
Anaprox Naproxen sodium 220-, 275-, 500-mg tablets 550 initial dose followed
Aleve by 220–275 q6–8 h or
550 q12 h
Nalfon Fenoprofen 200-mg capsules 200 q4–6 h
Orudis Ketoprofen 50-, 75-mg capsules 25–50 q6–8 h
Daypro Oxaprozin 600-mg tablet 600–1,200 q.d.
COX-2 inhibitors Celebrex Celecoxib 100-, 200-mg capsules 100–200 mg once or
twice daily
Table 7-3
Comparative Analgesic Efficacy of Commonly Used NSAIDs
NSAID Analgesic Efficacy Compared With Aspirin (650 mg)
Diflunisal 500 mg superior to aspirin, but has slower onset and longer duration; initial 1,000-mg
dose shortens time to onset
Choline–magnesium salicylate Longer duration of action
Ibuprofen Superior
Naproxen sodium 275 mg comparable with aspirin, but has slower onset and longer duration; 550 mg
superior to aspirin
Fenoprofen Comparable
Ketoprofen Superior
Indomethacin Comparable
Ketorolac tromethamine Superior
Data adapted from American Pain Society. Principles of analgesic use in the treatment of acute pain and chronic cancer pain, ed. 2. Clin Pharm 1990;9:601–611; and Forbes JA, Butterworth GA, Burchfield WH, et al. Evaluation of ketorolac, aspirin, and an acetaminophen-codeine combination in postoperative oral surgery pain. Pharmacotherapy 1990;10:775–935.
often underestimated. Use of nonsalicylate NSAIDs can be effective for intensely painful conditions, including post- operative pain, and can often avoid or delay the use of narcotic analgesics. Clinicians should note, however, that patients vary in their responses to individual analgesics. Thus, if patients do not respond to a particular drug at the maximum therapeutic dosage, an alternative analgesic should be used.
When instituting NSAID therapy, patients should be advised of the following: (1) the side effects of therapy, which can include GI discomfort and, rarely, more serious events such as GI bleeding; (2) to avoid aspirin and alco- holic beverages; and (3) to take the medication with food, milk, or antacids if GI upset occurs. The commercially available formulations and adult dosage recommendations are summarized in Table 7-2.
Side Effects
Side effects associated with the nonsalicylate NSAIDs are essentially those caused by salicylate therapy. NSAIDs occasionally cause CNS dysfunction, including decreased attention span, loss of short-term memory, confusion in elderly patients, and headache.
The adverse GI effects seen with aspirin can also occur with nonsalicylate NSAIDs. Although nonsalicylate NSAIDs may be tolerated in some patients who experi- ence GI side effects with aspirin, these patients should be monitored carefully for signs and symptoms of ulceration and bleeding. Patients with antecedent gastric ulcers, debilitating diseases, and advanced age appear to be most susceptible. It is not uncommon for patients to experi- ence minor GI complaints, such as dyspepsia, even after several days of therapy. Serious events such as ulceration, bleeding, or perforation can occur at any time with or without warning symptoms. Susceptible patients who require NSAID therapy should be given the lowest possi- ble therapeutic doses and those agents with the lowest side-effect profile to avoid aggravating or precipitating an adverse GI event. Several of the NSAIDs, including ibupro- fen, fenoprofen, diclofenac, nabumetone, and sulindac, appear to cause fewer GI effects than do other nonsalicy- late NSAIDs. On the other hand, piroxicam, ketoprofen, and especially azapropazone appear to have a relatively higher risk of serious GI complications. The differing gastric complications associated with various NSAIDs may be due to their varying relative selectivity for the two isoenzymes of cyclooxygenase: cyclooxygenase-1 (COX-1) versus COX-2. The products of COX-1 are cytoprotective in the kidney and in the gastric mucosa, whereas the COX-2 isoform appears responsible for the produc- tion of prostaglandins in inflammatory reactions.Antacid therapy with proton pump inhibitors may be useful to prevent or reduce NSAID-related dyspepsia and upper GI complications.
All nonsalicylate NSAIDs can inhibit platelet function. However, in contrast to aspirin, which has an irreversible effect on platelets, the nonsalicylate NSAIDs inhibit
platelet aggregation only as long as an effective serum drug concentration exists. Platelet function returns when most of the drug has been eliminated.
The nonsalicylate NSAIDs can also affect renal function. Risk factors for NSAID-induced acute renal failure include congestive heart failure, glomerulonephritis, chronic renal insufficiency, cirrhosis, systemic lupus erythematosus, diabetes mellitus, significant atherosclerotic disease in the elderly, and use of diuretics. NSAIDs can adversely affect cardiovascular homeostasis and can be a risk factor for the onset or exacerbation of heart failure.
Contraindications
Contraindications for nonsalicylate NSAID therapy are the same as those for aspirin (see Box 7-1).The formation of a gastric ulcer or erosion that may bleed profusely is a serious potential problem with NSAIDs. Consequently, the nonsalicylate NSAIDs should be avoided or used with great caution in patients with active peptic ulcer disease. NSAIDs may increase the risk of GI complications even when used in conjunction with low-dose aspirin for cardioprotection. In addition, because of potential cross- sensitivity to other NSAIDs, the nonsalicylate NSAIDs should not be given to patients in whom aspirin or other NSAIDs have caused symptoms of asthma, rhinitis, urticaria, angioedema, hypotension, bronchospasm, or of symptoms of hypersensitivity reactions. Opioids, tramadol, or acetaminophen may be suitable alternatives for patients with known or suspected susceptibility.
NSAIDs should be avoided in patients with chronic renal insufficiency due to the risk of inducing further kidney damage. In patients at risk, acute renal failure can occur after a single dose of drug. Risk factors include dehydration, hypertension, congestive heart failure, concomitant use of angiotensin-converting enzyme inhibitors, and advanced age.
Because the safe use of NSAIDs during pregnancy has not been well established, these agents should typically be avoided during pregnancy, especially in the third trimester. Likewise, these drugs should generally be avoided in nursing mothers, because most NSAIDs are excreted in breast milk and may have adverse effects on the cardiovascular system of nursing infants.
Acetaminophen
Acetaminophen is among the most commonly used anal- gesics in the United States. It is often the first drug used for management of mild to moderate pain, but it can also be of benefit in more severe pain when used as an