First-Generation Nonsteroidal Antiinflammatory Drugs (NSAIDs)
Second-Generation NSAID (Selective Cyclooxygenase-2 Inhibitor)
Drug That Lacks Antiinflammatory Actions
Aspirin is a highly valuable and effective medication. The drug provides excellent relief of mild to moderate pain, reduces fever, protects against thrombotic disorders, and remains a drug of choice for rheumatoid arthritis and other inflammatory conditions. Despite the introduction of many new NSAIDs, aspirin remains one of the most widely used members of the group and is the standard against which the others must be compared.
Aspirin belongs to a chemical family known as salicylates. All members of this group are derivatives of salicylic acid. Aspirin is produced by substituting an acetyl group onto salicylic acid. Because of this acetyl group, aspirin is commonly known as acetylsalicylic acid, or simply ASA.
Mechanism of Action
Aspirin is a nonselective inhibitor of cyclooxygenase. Most beneficial effects—reductions of inflammation, pain, and fever—result from inhibiting COX-2. One beneficial effect—protection against MI and ischemic stroke—results from inhibiting COX-1. Major adverse effects—gastric ulceration, bleeding, and renal impairment—result from inhibiting COX-1.
It is important to note that aspirin is an irreversible inhibitor of cyclooxygenase. In contrast, all other NSAIDs are reversible (competitive) inhibitors. Because inhibition of cyclooxygenase by aspirin is irreversible, duration of action depends on how quickly specific tissues can synthesize new molecules of COX-1 and COX-2. With other NSAIDs, effects decline as soon as drug levels fall.
Aspirin is absorbed rapidly and completely after oral dosing. The principal site of absorption is the small intestine. When administered by rectal suppository, aspirin is absorbed slowly, and blood levels are lower than with oral dosing.
Aspirin has a very short half-life (15–20 minutes) owing to rapid conversion to salicylic acid, an active metabolite. The rate of inactivation of salicylic acid depends on the amount present: at low therapeutic levels, salicylic acid has a half-life of approximately 2 hours, but at high therapeutic levels, the half-life may exceed 20 hours.
Salicylic acid is extensively bound to plasma albumin. At therapeutic levels, binding is between 80% and 90%. Aspirin undergoes distribution to all body tissues and fluids, including breast milk, fetal tissues, and the central nervous system (CNS).
Salicylic acid and its metabolites are excreted by the kidneys. Excretion of salicylic acid is highly dependent on urinary pH. Accordingly, by raising the pH of urine from 6 to 8, we can increase the rate of excretion fourfold.
Plasma Drug Levels
Low therapeutic doses of aspirin produce plasma salicylate levels less than100 mcg/mL. Antiinflammatory doses produce salicylate levels of about 150 to 300 mcg/mL. Signs of salicylism (toxicity) begin when plasma salicylate levels exceed 200 mcg/mL. Severe toxicity occurs at levels above 400 mcg/mL.
Aspirin is an initial drug of choice for rheumatoid arthritis, osteoarthritis, and juvenile arthritis. Aspirin is also indicated for other inflammatory disorders, including rheumatic fever, tendinitis, and bursitis. The dosages employed to suppress inflammation are considerably larger than dosages used for analgesia or reduction of fever. The use of aspirin and other NSAIDs to treat arthritis is discussed further in Chapter 57.
The precise mechanisms by which aspirin decreases inflammation have not been established. We do know that prostanoids contribute to several components of the inflammatory process. Hence inhibition of COX-2 provides a partial explanation of antiinflammatory effects. Other possible mechanisms include modulation of T-cell function, suppression of inflammatory cell infiltration, and stabilization of lysosomes.
Aspirin is used widely to relieve mild to moderate pain. The degree of analgesia produced depends on the type of pain. Aspirin is most active against joint pain, muscle pain, and headache. For some forms of postoperative pain, aspirin can be more effective than opioids. However, aspirin is relatively ineffective against severe pain of visceral origin. In contrast to opioid analgesics, aspirin produces neither tolerance nor physical dependence. In addition, aspirin is safer than opioids.
Aspirin relieves pain primarily through actions in the periphery. At sites of injury, prostanoids sensitize pain receptors to mechanical and chemical stimulation. Aspirin reduces pain by inhibiting COX-2, thereby suppressing prostanoid production. In addition to this peripheral mechanism, aspirin works in the CNS to help relieve pain.
Reduction of Fever
Aspirin is a drug of choice for reducing temperature in febrile adults. However, because of the risk for Reye syndrome (see later), aspirin should not be used to treat fever in children. Although aspirin readily reduces fever, it will not lower normal body temperature, nor will it lower temperature that has become elevated in response to physical activity or to a rise in environmental temperature.
Body temperature is regulated by the hypothalamus, which maintains a balance between heat production and heat loss. Fever occurs when the set point of the hypothalamus becomes elevated, causing the hypothalamus to increase heat production and decrease heat loss. Set-point elevation is triggered by local synthesis of prostaglandins in response to endogenous pyrogens (fever-promoting substances). Aspirin lowers the set point by inhibiting COX-2 and thereby inhibits pyrogen-induced synthesis of prostaglandins.
Aspirin can provide relief from primary dysmenorrhea. Benefits derive from inhibiting prostaglandin synthesis in uterine smooth muscle. (Prostaglandins promote uterine contraction, so suppression of prostaglandin synthesis relieves cramping.) Some of the newer aspirin-like drugs (e.g., ibuprofen, naproxen) are superior to aspirin for dysmenorrhea. The efficacy of the newer drugs is attributed to a greater ability to inhibit COX in the uterus.
Suppression of Platelet Aggregation
Synthesis of TXA2 in platelets promotes aggregation. Aspirin suppresses platelet aggregation by causing irreversible inhibition of COX-1, the enzyme that makes TXA2. Because platelets lack the machinery to synthesize new COX-1, the effects of a single dose persist for the life of the platelet (about 8 days).
There is a large body of evidence demonstrating that aspirin, through its antiplatelet actions, can benefit a variety of patients. Accordingly, the U.S. Food and Drug Administration (FDA) recommended wider use of aspirin for antiplatelet effects. Professional labeling now recommends daily aspirin for men and women with the following:
According to a review published in the Journal of the American Medical Association—“Aspirin Dose for the Prevention of Cardiovascular Disease”—a dose of 75 to 81 mg/day for these indications is adequate. Higher doses, which are commonly prescribed in these circumstances, offer no greater protection but will increase the risk for gastrointestinal (GI) bleeding.
In addition to these applications, aspirin can be taken by healthy people for primary prevention of MI and stroke. However, more recent studies show that aspirin provides less protection against cardiovascular disease than once thought. The potential small benefit must be weighed against the major risk of aspirin use, namely, GI hemorrhage. Hence, to determine the net benefit of primary prevention for any man or woman, we must determine his or her individual risk for a GI bleed and compare that risk with his or her individual risk for a cardiovascular event (i.e., the risk for an MI in men, or the risk for ischemic stroke in women).a Many organizations, including the American Heart Association (AHA), the American Thoracic Society, and the European Society of Cardiology, recommend against the use of aspirin for primary prevention of cardiovascular disease unless the patient has a 10-year risk greater than 10%.
How do we calculate 10-year risk for a cardiovascular event? Risk for an MI or stroke can be assessed using the calculator at cvdrisk.nhlbi.nih.gov/.
There is good evidence that regular use of aspirin decreases the risk for colorectal cancer, even when the dosage is low. Results from the Nurses’ Health Study showed that regular use of high-dose aspirin (650 mg/day or more) reduces the risk for colorectal cancer. This dosage is much greater than that used to prevent cardiovascular disease and hence poses a significant risk for bleeding. In fact, for every one or two cancers prevented, high-dose aspirin would cause eight additional serious bleeds. Fortunately, more recent studies indicate that low-dose aspirin is effective, too. For example, results of a study reported in The Lancet in 2010 indicate that taking low-dose aspirin (75–300 mg/day) for more than 5 years reduces the incidence of colorectal cancer (by 24%) as well as mortality from colon cancer (by 35%). At these low doses, the benefits of cancer protection may well outweigh the risk for possible bleeding and other adverse events.
Aspirin protects against colorectal cancer probably by inhibiting COX-2. In animal models, COX-2 promotes tumor growth and metastases, and inhibition of COX-2 slows tumor growth. In humans, most colorectal cancers express COX-2. Furthermore, protection by aspirin is limited to colon cancers that have high COX-2 levels. Aspirin does not protect against colon cancers with little or no COX-2.
Available data suggest that protection may not be limited to colorectal cancer. Results of a meta-analysis reported in The Lancet, “Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials,” show that daily low-dose aspirin reduces the risk for death from all solid tumors (by 34%), but does not reduce the risk for death from hematologic cancers. In addition, The Lancet published an additional article in 2012 that analyzed 5 randomized controlled trials. This analysis determined that use of aspirin may also prevent distant metastasis of tumors that already exist. Earlier studies have shown protection against specific cancers. In a study involving men older than 60 years, daily use of aspirin and other NSAIDs was associated with a 50% decrease in the incidence of prostate cancer. In a study involving 2884 women, aspirin appeared to reduce the risk for breast cancer, especially among women with hormone receptor–positive tumors and among those who took 7 or more aspirin tablets a week. In another study, taking aspirin at least 3 times a week for at least 6 months was associated with a 40% reduction in the incidence of ovarian cancer. In contrast to these positive results, results from the Women’s Health Study found no protection with low-dose aspirin against cancer of the breast, colon, or any other tissue. The reasons for this discrepancy are not clear. Four additional studies are currently underway to examine various effects of aspirin on cancer prevention.
When administered short term in analgesic or antipyretic (fever-reducing) doses, aspirin rarely causes serious adverse effects. However, toxicity is common when treating inflammatory disorders, which require long-term high-dose treatment.
The most common side effects are gastric distress, heartburn, and nausea. These can be reduced by taking aspirin with food or a full glass of water.
Occult GI bleeding occurs often. In most cases, the amount of blood lost each day is insignificant. However, with chronic aspirin use, cumulative blood loss can produce anemia.
Long-term aspirin—even in low doses—can cause life-threatening gastric ulceration, perforation, and bleeding. Ulcers result from four causes:
The first three occur secondary to inhibition of COX-1. Direct injury to the stomach is most likely with aspirin preparations that dissolve slowly: owing to slow dissolution, particulate aspirin becomes entrapped in folds of the stomach wall, causing prolonged exposure to high concentrations of the drug. Because aspirin-induced ulcers are often asymptomatic, perforation and upper GI hemorrhage can occur without premonitory signs. (Hemorrhage is due in part to erosion of the stomach wall and in part to suppression of platelet aggregation.) Factors that increase the risk for ulceration include the following:
What can we do to prevent ulcers? According to an expert panel—convened in 2008 by the American College of Gastroenterology, the AHA, and the American College of Cardiology—prophylaxis with a proton pump inhibitor (PPI) is recommended for patients at risk, including those with a history of peptic ulcers, those taking glucocorticoids, and older adults. Proton pump inhibitors (e.g., omeprazole, lansoprazole) reduce ulcer generation by suppressing production of gastric acid. In addition to PPIs, other drugs that may be considered include histamine-2 receptor antagonists (H2RAs) and misoprostol. COX-2 inhibitors may also be tried instead of traditional NSAIDs because they are thought to produce fewer GI side effects. Because many ulcers are caused by infection with Helicobacter pylori (see Chapter 62), the panel recommends that patients with ulcer histories undergo testing and treatment for H. pylori before starting long-term aspirin use. Treatment of NSAID-induced ulcers is discussed in Chapter 62.
Aspirin promotes bleeding by inhibiting platelet aggregation. Taking just two 325-mg aspirin tablets can double bleeding time for about 1 week. (Recall that platelets are unable to replace aspirin-inactivated cyclooxygenase, and hence bleeding time is prolonged for the life of the platelet.) Because of its effects on platelets, aspirin is contraindicated for patients with bleeding disorders (e.g., hemophilia, vitamin K deficiency, hypoprothrombinemia). To minimize blood loss during childbirth and elective surgery, high-dose aspirin should be discontinued at least 1 week before these procedures. There is no need to stop aspirin before procedures with a low risk for bleeding (e.g., dental, dermatologic, or cataract surgery). In most cases, use of low-dose aspirin to protect against thrombosis should not be interrupted for elective surgery and dental procedures. Caution is needed when aspirin is used in conjunction with anticoagulants.
In patients taking daily aspirin, high blood pressure increases the risk for hemorrhagic stroke, even though aspirin protects against ischemic stroke. To reduce risk for hemorrhagic stroke, blood pressure should be 150/90 mm Hg (and preferably lower) before starting daily aspirin.
Aspirin can cause acute, reversible impairment of renal function, resulting in salt and water retention and edema. Clinically significant effects are most likely in patients with additional risk factors: advanced age, existing renal impairment, hypovolemia, hepatic cirrhosis, or heart failure. Aspirin impairs renal function by inhibiting COX-1, thereby depriving the kidney of prostaglandins needed for normal function.
Development of renal impairment is signaled by reduced urine output, weight gain despite use of diuretics, and a rapid rise in serum creatinine and blood urea nitrogen. If any of these occurs, aspirin should be withdrawn immediately. In most cases, kidney function then returns to baseline level.
The risk for acute renal impairment can be reduced by identifying high-risk patients and treating them with the smallest dosages possible.
In addition to its acute effects on renal function, aspirin may pose a risk for renal papillary necrosis and other types of renal injury when used long term.
Salicylism is a syndrome that begins to develop when aspirin levels climb just slightly above therapeutic. Overt signs include tinnitus, sweating, headache, and dizziness. Acid-base disturbance may also occur (see later). If salicylism develops, aspirin should be withheld until symptoms subside. Aspirin should then resume, but with a small reduction in dosage. In some cases, development of tinnitus can be used to adjust aspirin dosage: when tinnitus occurs, the maximal acceptable dose has been achieved. However, this guideline may be inappropriate for older patients because they may fail to develop tinnitus even when aspirin levels become toxic.
Acid-base disturbance results from the effects of aspirin on respiration. When administered in high therapeutic doses, aspirin acts on the CNS to stimulate breathing. The resultant increase in CO2 loss produces respiratory alkalosis. In response, the kidneys excrete more bicarbonate. There is also a subsequent buildup of acids, producing a resultant metabolic acidosis. Thus many patients that present with salicylate toxicity will have a mixed acid-base imbalance.
Use of aspirin in children younger than 18 years is associated with Reye syndrome.
This syndrome is a rare but serious illness of childhood that has a mortality rate of 20% to 30%. Characteristic symptoms are encephalopathy and fatty liver degeneration. Epidemiologic data suggested a relationship between Reye syndrome and use of aspirin by children who have influenza or chickenpox. Although a direct causal link between aspirin and Reye syndrome was never established, the Centers for Disease Control and Prevention recommended that aspirin (and other NSAIDs) be avoided by children and teenagers suspected of having influenza or chickenpox. In response to this recommendation, aspirin was removed from most products intended for children, and aspirin use by children declined sharply. As a result, Reye syndrome essentially vanished: the incidence declined from a high of 555 cases in 1980 to no more than 2 cases per year since 1994. If a child with chickenpox or influenza needs an analgesic-antipyretic, acetaminophen can be used safely.
Adverse Effects Associated With Use During Pregnancy
Aspirin poses risks to the pregnant patient and her fetus. Accordingly, the drug is classified in FDA Pregnancy Risk Category D: there is evidence of human fetal risk, but the potential benefits from use of the drug during pregnancy may outweigh the potential for harm. The principal risks to pregnant women are (1) anemia (from GI blood loss) and (2) postpartum hemorrhage. In addition, by inhibiting prostaglandin synthesis, aspirin may suppress spontaneous uterine contractions and may thereby prolong labor.
Aspirin crosses the placenta and may adversely affect the fetus. Because prostaglandins help keep the ductus arteriosus patent, inhibition of prostaglandin synthesis by aspirin may induce premature closure of the ductus arteriosus. Aspirin use has also been associated with low birth weight, stillbirth, renal toxicity, intracranial hemorrhage in preterm infants, and neonatal death.
Hypersensitivity develops in about 0.3% of aspirin users. Reactions are most likely in adults with a history of asthma, rhinitis, and nasal polyps. Hypersensitivity reactions are uncommon in children. The aspirin hypersensitivity reaction begins with profuse, watery rhinorrhea and may progress to generalized urticaria, bronchospasm, laryngeal edema, and shock. Despite its resemblance to severe anaphylaxis, this reaction is not allergic and is not mediated by the immune system. What does cause these reactions? Because individuals who react to aspirin are also sensitive to most other NSAIDs, we believe that the reactions are due to inhibition of COX-1, which triggers production of leukotrienes, which in turn causes bronchospasm, hives, and other signs of hypersensitivity. However, if this is the mechanism, it remains unclear why hypersensitivity is limited mainly to adults with the predisposing conditions noted earlier. As with severe anaphylactic reactions, epinephrine is the treatment of choice.
Hypersensitivity to aspirin is considered a contraindication to using other drugs with aspirin-like properties. Nonetheless, if an aspirin-like drug must be taken, four such drugs are probably safe. One of these—celecoxib—is selective for COX-2. Another—meloxicam—is somewhat selective for COX-2, but only at low doses. The other two—acetaminophen and salsalate—are only weak inhibitors of COX-1.
In contrast to all other NSAIDs, aspirin does NOT increase the risk for thrombotic events, including MI and ischemic stroke. In fact, when taken in low doses, aspirin protects against these events.
Daily use of aspirin and other NSAIDs is associated with a 22% increase in the risk for erectile dysfunction, as shown in a study of 80,966 men in California. However, a causal relationship has not been established.
Summary of Precautions and Contraindications
Aspirin is contraindicated in patients with peptic ulcer disease, bleeding disorders (e.g., hemophilia, vitamin K deficiency, hypoprothrombinemia), and hypersensitivity to aspirin itself or other NSAIDs. In addition, the drug should be used with extreme caution by pregnant women and by children who have chickenpox or influenza. Caution should also be exercised when treating older-adult patients, patients who smoke cigarettes, and patients with H. pylori infection, heart failure, hepatic cirrhosis, hypovolemia, renal dysfunction, asthma, hay fever, chronic urticaria, nasal polyps, or a history of alcoholism. Aspirin should be withdrawn 1 week before elective surgery or the anticipated date of childbirth.
PATIENT-CENTERED CARE ACROSS THE LIFE SPAN
Nonsteroidal Antiinflammatory Drugs
|Life Stage||Patient Care Concerns|
|Infants||Because of the risk for Reye syndrome, aspirin should be avoided in infants. Acetaminophen and ibuprofen can be used safely in small doses for fever.|
|Children/adolescents||Because of the risk for Reye syndrome, aspirin should be avoided in children and adolescents. Acetaminophen and ibuprofen can be used safely in small doses for fever.|
|Pregnant women||NSAIDs may result in premature closure of the ductus arteriosus. Therefore their use is contraindicated in the third trimester of pregnancy.|
|Breastfeeding women||NSAIDs and acetaminophen appear safe for use in breastfeeding mothers.|
|Older adults||NSAIDs are the most common drug used to treat chronic pain in older adults. These drugs have been shown to increase hospital admissions in this population. Caution should be used with NSAIDs in older adults.|
Because of its widespread use, aspirin has been reported to interact with many other medications. However, most of these interactions have little clinical significance. Significant interactions are discussed next.
Anticoagulants: Warfarin, Heparin, and Others
Aspirin’s most important interactions are with anticoagulants. Because aspirin suppresses platelet function and can decrease prothrombin production, aspirin can intensify the effects of warfarin, heparin, and other anticoagulants. Furthermore, because aspirin can initiate gastric bleeding, augmenting anticoagulant effects can increase the risk for gastric hemorrhage. Accordingly, the combination of aspirin with anticoagulants must be used with care—even when aspirin is taken in low doses to reduce the risk for thrombotic events.
Like aspirin, glucocorticoids promote gastric ulceration. As a result, the risk for ulcers is greatly increased when these drugs are combined—as may happen when treating arthritis. To reduce the risk for gastric ulceration, patients can be given a PPI or H2RA for prophylaxis.
Combining alcohol with aspirin and other NSAIDs increases the risk for gastric bleeding. To alert the public to this risk, the FDA now requires that labels for aspirin include the following statement: Alcohol Warning: If you consume three or more alcoholic drinks every day, ask your doctor whether you should take aspirin or other pain relievers/fever reducers. Aspirin [and related drugs] may cause stomach bleeding. A similar label is required for all other NSAIDs and acetaminophen.
Ibuprofen, naproxen, and other nonaspirin NSAIDs can reduce the antiplatelet effects of aspirin by blocking access of aspirin to COX-1 in platelets. This interaction is important: in patients taking low-dose aspirin to prevent MI or ischemic stroke, other NSAIDs could negate aspirin’s benefits. Because immediate-release aspirin produces complete platelet inhibition about 1 hour after dosing, we can prevent interference by giving aspirin about 2 hours before giving other NSAIDs. Of course, we could eliminate interference entirely by using high-dose aspirin, rather than another NSAID, when conditions call for NSAID therapy.
ACE Inhibitors and ARBs
Like aspirin, angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) can impair renal function. In susceptible patients, combining aspirin with drugs in either class can increase the risk for acute renal failure. High-dose aspirin should be avoided in patients taking these drugs. However, low-dose aspirin taken for antiplatelet effects should be continued.
Aspirin and other NSAIDs may blunt the immune response to vaccines. Accordingly, these drugs should not be used routinely to prevent vaccination-associated fever and pain.
Aspirin overdose is a common cause of poisoning. Although rarely fatal in adults, aspirin poisoning may be lethal in children. The lethal dose for adults is 20 to 25 g. In contrast, as little as 4000 mg (4 g) can kill a child.
Signs and Symptoms
Initially, aspirin overdose produces a state of compensated respiratory alkalosis—the same state seen in mild salicylism. As poisoning progresses, respiratory excitation is replaced with respiratory depression. Acidosis, hyperthermia, sweating, and dehydration are prominent, and electrolyte imbalance is likely. Stupor and coma result from effects in the CNS. Death usually results from respiratory failure.
Aspirin poisoning is an acute medical emergency that requires hospitalization. The immediate threats to life are respiratory depression, hyperthermia, dehydration, and acidosis. Treatment is largely supportive. If respiration is inadequate, mechanical ventilation should be instituted. External cooling (e.g., sponging with tepid water) can help reduce hyperthermia. Intravenous fluids are given to correct dehydration; the composition of these fluids is determined by electrolyte and acid-base status. Slow infusion of bicarbonate is given to reverse acidosis. Several measures (e.g., gastric lavage, giving activated charcoal) can reduce further GI absorption of aspirin. Alkalinization of the urine with bicarbonate accelerates excretion of aspirin and salicylate. If necessary, hemodialysis or peritoneal dialysis can be used to remove salicylates.
Aspirin is available in multiple formulations, including plain and buffered tablets, enteric-coated preparations, and tablets used to produce a buffered solution. These different formulations reflect efforts to increase rates of absorption and decrease gastric irritation. For the most part, the clinical utility of the more complex formulations is no greater than that of plain aspirin tablets.
Aspirin Tablets, Plain
All brands are essentially the same with respect to analgesic efficacy, onset, and duration. Some less expensive tablets have greater particle size, which results in slower dissolution and prolonged contact with the gastric mucosa, which increases gastric irritation. When aspirin tablets decompose, they smell like vinegar (acetic acid) and should be discarded.
Aspirin Tablets, Buffered
The amount of buffer in buffered aspirin tablets is too small to produce significant elevation of gastric pH. An equivalent effect on pH can be achieved by taking plain aspirin tablets with food or a glass of water. Buffered aspirin tablets are no different from plain tablets with respect to analgesic effects and gastric distress. Buffered tablets may dissolve faster than plain tablets, resulting in somewhat faster onset.
Buffered Aspirin Solution
A buffered aspirin solution is produced by dissolving effervescent aspirin tablets [Alka-Seltzer] in a glass of water. This solution has considerable buffering capacity owing to its high content of sodium bicarbonate. Effects on gastric pH are sufficient to decrease the incidence of gastric irritation and bleeding. In addition, aspirin absorption is accelerated and peak blood levels are raised. Unfortunately, these benefits come with a price. The sodium content of buffered aspirin solution can be detrimental to individuals on a sodium-restricted diet. Also, absorption of bicarbonate can elevate urinary pH, which will accelerate aspirin excretion. Lastly, this highly buffered preparation is expensive. Because of this combination of benefits and drawbacks, the buffered aspirin solution is well suited for occasional use but is generally inappropriate for long-term therapy.
Enteric-coated preparations dissolve in the intestine rather than the stomach, thereby reducing gastric irritation. Unfortunately, absorption from these formulations can be delayed and erratic. Patients should be advised not to crush or chew them.