Side Effects

The major side effects of NSAIDs are gastrointestinal and include dyspepsia, heartburn, nausea, vomiting, abdominal pain, peptic ulcer, and gastrointestinal bleeding.

Prostaglandins stimulate the secretion of a protective mucosal layer in the gastrointestinal tract. Inhibition of these prostaglandins leads to a breakdown of this mucosal layer, which leads to ulceration. Aspirin, when administered without an enteric coating, buffers, or antacids, causes increased entry of acid into the gastric mucosa, leading to cellular damage at the site of dissolution. As mentioned previously, enteric-coated aspirin will undergo dissolution in the small intestine, thereby avoiding the direct effect on the gastric lining. The administration of NSAIDs with food or milk will minimize adverse gastrointestinal effects. Coadministration of aspirin and other NSAIDs with corticosteroids increases the risk of gastrointestinal lesions. Alcohol consumption concomitant with the intake of aspirin or NSAIDs may put patients at increased risk of upper gastrointestinal bleeding, a risk that is elevated by increasing alcohol consumption.3,4

Aspirin, salicylates, and to a much lesser extent NSAIDs have hematological effects that must be considered in the athlete. Aspirin inhibits platelet aggregation and decreases hepatic synthesis of blood coagulation factors. At normal doses of up to 6 g/day, aspirin rarely increases the prothrombin time (PT), the time it takes blood to clot, by more than 2 to 3 seconds. Higher doses, fever, and increased metabolic rate may cause greater increases in PT. For athletes in contact sports, especially when the likelihood of head trauma is high, aspirin may not be a good therapeutic choice. Head trauma occurring in an athlete in an anticoagulated state might increase the risk or extent of intracranial bleeding. Research is mixed on the probability of aspirin causing increased intracranial bleeding after head trauma for the patient who is receiving low-dose aspirin therapy.⁵

Other NSAIDs, such as ibuprofen, inhibit platelet aggregation but to a lesser extent than aspirin. This has raised some concern that NSAIDs not be used by athletes in sports that may put the athletes at risk for head trauma. Physicians have various views on this subject.⁵ Health care providers working with athletes in contact or collision sports have a responsibility to know and uphold the views of the team physicians on this subject.

Renal effects of NSAIDs are also of concern. Prostaglandins play a role in maintaining renal perfusion in individuals with certain renal conditions. An athlete receiving long-term NSAID therapy who becomes dehydrated may be at risk for renal impairment and needs to be monitored for symptoms of azotemia, such as malaise, fatigue, or loss of appetite.

Other adverse effects of NSAIDs include rashes, dermatitis, photosensitivity (requiring the use of sun block), dizziness, headache, nervousness, fatigue, drowsiness, fluid retention, anaphylaxis, bronchospasm, tinnitus, and visual disturbances. These symptoms are relatively rare in patients, and represent only patients who have serious allergic reactions to NSAIDs.

The safety of the COX-2 inhibitors has been questioned with the industry withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra), due to increased risk of cardiovascular events.6–8 At this time, celecoxib (Celebrex) remains the only COX-2 inhibitor available for use by patients. Previous meta-analyses revealed that all nonselective NSAIDs may have increased cardiovascular risks, although the risks are relatively low when compared with the number of patients taking these medications. The athletic trainer and general consumer must remember that along with the benefits, potential adverse effects occur with any drug. Individual patient needs and risk factors must be considered to make the best drug therapy choices. The lowest possible effective dose should always be used to minimize the chance of adverse drug events.

Contraindications

NSAIDs are contraindicated for individuals who have had a previous hypersensitivity reaction or other severe allergic reaction to aspirin or any other NSAID and for individuals who have experienced bronchospasm or angioedema when taking aspirin or other NSAIDs, or who have nasal polyps. Extreme caution is needed when giving aspirin or other NSAIDs to individuals with a history of gastrointestinal lesions (e.g., peptic ulcer), athletes who have sickle cell anemia, and those taking blood thinners such as enoxaparin (Lovenox) or warfarin (Coumadin).

Interactions

Because many NSAIDs are readily available over the counter, the athlete may be tempted to take NSAIDs such as ibuprofen with acetaminophen.⁹ These two drugs have different mechanisms of action, and therefore it is safe to combine them if the maximum dosage of over-the-counter NSAIDs is not providing enough analgesia. The athletic trainer is strongly encouraged to monitor the medication intake of all athletes, regardless of whether the medication is available without a prescription.¹⁰ If the athlete’s discomfort is not relieved, the team physician should be consulted about the condition. The athletic trainer also needs to educate the athlete that many products contain the same active ingredients and therefore care must be taken when taking medications of any kind.

Side Effects

The side effects of corticosteroids depend on the dose and the route of administration. They are minimal with intrasynovial injection, intraarticular injection, intranasal application, inhalation, or short-term therapy. However, tendon ruptures have occurred in patients receiving corticosteroid injections. The Achilles tendon is especially susceptible to this effect. Research indicates that repeated short courses, intranasal corticosteroids, and inhaled corticosteroids may also cause decreased bone density and osteoporosis.16,17

For orally administered short-course tapers, the most common side effects are increased appetite, restlessness, insomnia, fluid retention, gastrointestinal disturbances, and decreased glucose tolerance. Gastrointestinal effects are diminished if doses are taken along with food. Less common but serious effects of corticosteroids include the development of and impaired healing of peptic ulcers.

In addition, high doses or prolonged use of corticosteroids used for treatment of systemic inflammatory or autoimmune diseases, such as lupus, multiple sclerosis, or inflammatory bowel syndromes (e.g., Crohn’s disease), may produce devastating side effects. These may include changes in physical appearance caused by changes in fat deposition, adrenal suppression, cataracts, or peptic ulcers. Long-term use of corticosteroids may lead to decreased bone density and osteoporosis.¹⁶

In the diabetic athlete, corticosteroids, even when used briefly, must be taken with caution because of their effects on glucose tolerance. Changes in insulin doses or diet may be required in diabetic individuals during treatment with corticosteroids.

Corticosteroids, including those administered intranasally, may cause a reduction in growth velocity in pediatric patients but have no impact on final adult height.¹⁶ The growth of pediatric patients receiving corticosteroids should be monitored routinely. In addition, in order to prevent decreases in bone density, children older than 11 years of age should receive calcium, 1500 mg/day, and vitamin D, 800 IU/day, throughout the course of treatment with corticosteroids.¹⁷

Repeated intrasynovial or intraarticular injection will not result in any systemic effects but will cause damage to the joint. Intraarticular injections in major weight-bearing joints are not recommended because of the potential softening of joint cartilage.¹⁷ Even after a single injection, if the joint is not allowed proper time to heal, damage may occur. Consideration of the potential risks to the joint must be considered and discussed with the patient before intraarticular injection.

Intranasal corticosteroids are generally very well tolerated. The most common side effects are nasal irritation, pharyngeal irritation, and dryness. Similarly, the most common side effects of inhaled corticosteroids are hoarseness, dry mouth, sore throat, and oropharyngeal fungal infections, such as Candida albicans or Aspergillus niger.² After using an inhaled corticosteroid, the mouth should always be rinsed to prevent oral fungal infections.

Side Effects

The main adverse effects of bronchodilators are tremor, nervousness, dizziness, headache, nausea, and tachycardia. A paradoxical bronchospasm also has been reported in 8% of individuals using bronchodilators.18,19 It is usually associated with the first use of a new MDI canister and may be related to exposure to the propellant. To avoid this reaction, a new MDI can be actuated into the air a few times before its first use. Nebulized albuterol caused coughing in 4% of individuals in various clinical trials. Side effects that occurred in less than 3% of individuals but that may be significant in the athlete include muscle cramping, muscle spasm, and dilated pupils.¹⁸

Levalbuterol (Xopenex) is the R-enantiomer of albuterol. It is available only as a solution for nebulization. Levalbuterol is considerably more expensive than albuterol, but it is associated with a lower rate of adverse effects. For treating exercise-induced asthma in the athlete, albuterol, the less expensive alternative, is the medication of choice.

Leukotriene-modifying Respiratory Medications

Leukotriene-modifying medications are either competitive antagonists of leukotriene receptors or inhibitors of leukotriene synthesis²⁰. Leukotriene receptor antagonists inhibit the action of leukotrienes, which are potent constrictors of bronchial smooth muscle. These medications include zafirlukast (Accolate) and montelukast (Singulair). Leukotriene inhibitors prevent the formation of 5-lipoxygenase, which catalyzes the formation of leukotrienes from arachidonic acid. The medication zileuton (Zyflo) represents this class of medication. Both classes of leukotriene-modifying medications display efficacy in the treatment of asthma,²¹ but are generally not effective for the treatment of EIB,²¹ and are not replacements for short-acting β-agonists when treating EIB.

Mast Cell–stabilizing Medications

Mast cell-stabilizing medications are recognized for their ability to inhibit the release of histamine from bronchial mast cells, as well as attenuating cough reflexes. Cromolyn and nedocromil are effective for treating athletes with known EIB; they are generally used continuously for the prevention of EIB. These medications are considered to be less potent in controlling asthma than other agents. Cromolyn is also available as a nasal inhalant solution to treat allergic rhinitis symptoms.

Anticholinergic Agents

Bronchodilation is achieved with anticholinergic medications used for the treatment of asthma. These medications relax bronchial smooth muscle through competitive antagonism of muscarinic receptors present in the lungs. There are short-acting (ipratropium) and long-acting (tiotropium) respiratory anticholinergics, which are both effective for asthma and chronic obstructive pulmonary disease (COPD). In some athletes, these agents may be effective for prevention of EIB when used before exercise.²²

Antihistamines

Antihistamines are drugs used to treat allergies. When the body’s immune system reacts to an allergen, histamine is released by the mast cells and basophils. Histamine binds to histamine receptors in the nose, eyes, respiratory tract, and skin, causing the classic allergic signs (e.g., rhinitis, sneezing, watery eyes, itching, dermatitis). Antihistamines are antagonists that block the histamine receptors and prevent histamine from binding to the cell’s receptors.

The histamine antagonists are classified into two groups on the basis of their likelihood of causing sedation. The first-generation, or sedating, antihistamines are older agents with a much higher incidence of anticholinergic adverse effects, including sedation (Table 5-5). They are used in the treatment of seasonal allergies and some cold symptoms. The sedating properties associated with these drugs also make them useful in the short-term treatment of insomnia. In addition, some antihistamines, such as meclizine (Antivert) and hydroxyzine (Atarax, Vistaril), are used in the treatment of nausea, vertigo, motion sickness, and hives. Sedating antihistamines are commonly used to treat allergy symptoms associated with seasonal allergies and are usually formulated in combination with decongestants.

Nonsedating, or second-generation, antihistamines are used to treat and prevent seasonal allergies and to treat chronic idiopathic urticaria. These antihistamines are often the drug of choice for the athlete because they are nonsedating (Table 5-6). The nonsedating antihistamines currently available by prescription are fexofenadine (Allegra) and desloratadine (Clarinex). Cetirizine (Zyrtec) and loratadine (Claritin, Alavert) are now available as over-the-counter products. Cetirizine and fexofenadine are also formulated in combination with the decongestant pseudoephedrine (Zyrtec-D, Allegra-D).

The adverse effects most often associated with the first-generation sedating antihistamines are those caused by central nervous system (CNS) depression, such as drowsiness, muscular weakness, and dizziness. Therefore antihistamines should be used with caution in athletes participating in events where coordination and alertness are needed to prevent injury. The incidence of injury may be increased and performance decreased even with a mild sedative effect from the antihistamine. Anyone taking antihistamines should avoid alcohol intake because of the additive effect on CNS depression.²

Additional adverse effects seen with first-generation antihistamines may be gastrointestinal in nature and include nausea, vomiting, diarrhea, and constipation. These antihistamines also cause anticholinergic side effects, such as dry mouth, blurred vision, urinary retention, impotence, nervousness, and irritability.¹

Antihistamines must be used with caution in individuals with hypertension and hyperthyroidism (see Chapters 8 and 14). Because there is some controversy over the potential for antihistamines to induce asthma attacks by virtue of their drying effect on bronchial tissues, antihistamines are contraindicated in individuals who experience acute asthmatic attacks. The drug interactions of the sedating antihistamines are primarily with other CNS depressants, which will cause an additive CNS depressant effect.

Decongestants

Decongestants are medications that stimulate primarily the α-adrenergic receptors and to a lesser extent the β-adrenergic receptors (Table 5-7). The beneficial result of this α-adrenergic stimulation is vasoconstriction in the nasal mucosa, which shrinks swollen nasal passages and thereby relieves nasal congestion. The decongestants are used orally either alone or in combination with other agents used to treat cold and allergy symptoms (e.g., antihistamines).

Topical decongestants can also be applied directly to the nasal mucosa (e.g., Afrin) to provide relief from congestion without systemic side effects. Ophthalmic decongestants (e.g., Visine) are applied to the eye to produce vasoconstriction of the conjunctival vasculature, reducing redness of the eyes.

Pseudoephedrine (Sudafed) is the oral decongestant most commonly used alone or in combination products. Pseudoephedrine is a naturally occurring substance found in plants of the genus Ephedra and is an isomer of ephedrine. The usual adult dose of pseudoephedrine is 30 to 60 mg every 4 to 6 hours. Sustained-release products of pseudoephedrine are available as 120 mg tablets given every 12 hours and 240 mg tablets given every 24 hours.² The side effects associated with the use of pseudoephedrine include mild CNS stimulation such as nervousness, dizziness, weakness, insomnia, and headache. Whereas pseudoephedrine causes minimal blood pressure changes in individuals with normal blood pressure, it should be used with caution in individuals with high blood pressure because α-adrenergic stimulation causes vasoconstriction and may raise blood pressure.

Pseudoephedrine can be used to make methamphetamine, a CNS stimulant with high addictive potential. For this reason, federal law limits the quantity of pseudoephedrine that can be sold by retail distributors. However, it is important that the athletic trainer be aware that the oral decongestants pseudoephedrine and phenylephrine are no longer listed in the National Collegiate Athletic Association (NCAA) bylaws (Section 31.2.3) as banned drugs.²³ It should be noted that other CNS stimulants remain on the banned substances list.²³

Phenylephrine (Neo-Synephrine) is used as a topical decongestant in nasal drops and sprays. It, too, is no longer listed on the NCAA list of banned drugs.²³ Phenylephrine nasal drops or sprays for adults are available as 0.25% or 0.5% solutions that are applied to the nasal mucosa every 4 to 6 hours. Adverse effects of phenylephrine nasal solutions include transient burning, stinging, sneezing, rhinitis, and nasal dryness. Prolonged use of phenylephrine nasal solutions should be avoided because it may result in chronic or rebound swelling of the nasal mucosa, which resolves within 1 week of discontinuing the drug.

Oxymetazoline (Afrin, Dristan) and xylometazoline (Otrivin) are long-acting topical decongestants found in nasal sprays and drops. These long-acting agents should not be used for more than 3 days because significant rebound congestion frequently occurs and may promote overuse of these drugs.

Ophthalmic decongestants, such as tetrahydrozoline (Visine), provide relieve of conjunctival redness and minor eye irritation. Prolonged use of ophthalmic decongestant solutions must be avoided, however, because rebound hyperemia may result and promote overuse of the products. It is also important that use of ophthalmic decongestants not mask an underlying condition that may need medical attention. If ocular pain, redness, or irritation occurs or if visual changes are experienced during the use of these products, the athlete must discontinue use immediately and seek medical attention.

Individuals with glaucoma should not use ophthalmic decongestants without consulting a physician or optometrist. Also, most manufacturers recommend that contact lenses be removed before using any ophthalmic decongestant product. Whereas allergic reactions to the ophthalmic decongestants themselves are extremely rare, allergic reactions to the preservatives used in these products are common.