The Safety of NSAIDs and Related Drugs for the Management of Acute Pain: Maximizing Benefits and Minimizing Risks

The short-term management of pain is one of the conditions that most frequently confront physicians in the clinic. Our dilemma is choosing the most effective treatment that is associated with few side effects.

There is a general consensus among physicians that the treatment of pain is inadequate.¹ In addition, many physicians are concerned about the side effects of both opioid and non-opioid analgesics. Prescribing opioid agents carries the physician into an environment in which legal and societal pressures exist, and these pressures discourage the liberal use of opioids. This scenario may explain in part why the most frequently prescribed treatment for pain is nonsteroidal anti-inflammatory drugs (NSAIDs).²

Used for the management of several different symptoms and numerous conditions, NSAIDs continue to be among the most frequently prescribed medications. Approximately 100 million prescriptions for this class of drugs are written each year. While their benefits are unquestionable, physicians generally recognize that the use of NSAIDs is associated with a number of important side effects, including gastrointestinal (GI) and renal toxicity.

NSAIDs function via a number of different mechanisms. However, the mechanism that may be the most frequently discussed, and perhaps the one associated with the greatest number of potential side effects, involves the inhibition of prostaglandin biosynthesis, described by Vane in 1971.³

The inhibition of prostaglandin biosynthesis in the periphery and the abrogation of nociception are effective methods of diminishing pain perception. However, the prudent use of NSAIDs requires cognizance of potential side effects. Clinical experience suggests that, although complications can occur early in the course of treatment, they are more likely to occur with chronic use.

Gastrointestinal toxicity is the most frequently encountered side effect associated with NSAIDs and presents considerable concern. Approximately one half of all hospital admissions for a bleeding ulcer are attributed to the use of NSAIDs, aspirin, or the two taken in combination during the week prior to admission.⁴ A survey of Tennessee Medicaid patients who were hospitalized with GI complications showed that patients who used NSAIDs had approximately a fourfold greater risk for developing GI hemorrhage or peptic ulcer disease than patients not taking NSAIDs.⁵ Serious GI events, according to the FDA, occur in as many as 2% to 4% of patients per year who are taking continuous NSAID therapy for rheumatoid arthritis. The relative risk of gastric ulcer (4.725), duodenal ulcer (1.1 to 1.6), bleeding (3.8), perforation, and death are all increased by NSAID use when such patients are compared to those who do not take these products. In 1989, patients with rheumatoid arthritis had approximately 20,000 hospitalizations per year with an estimated cost of $10,000 per stay.⁶ Some currently available NSAIDs that are more COX-2 selective, such as etodolac and nabumetone, may be associated with less risk of GI toxicity.⁷ Newer agents such as celecoxib and rofecoxib are even more selective and therefore may be associated with even fewer side effects.

Patients at increased risk of developing GI complications include those with a prior history of peptic ulcer and especially those with prior upper GI bleeding, regardless of the source. These patients had a relative risk of 13.5 for a recurrent complication.⁸

Renal complications are the second greatest concern associated with NSAID use. Renal side effects include fluid and electrolyte disturbances such as sodium and water retention and/or hyperkalemia. Acute renal failure, nephrotic syndrome with acute interstitial nephritis, and papillary necrosis may also occur.⁹ Renal prostaglandins with other mediators help to maintain normal renal homeostasis, and when prostaglandins are inhibited by the use of NSAIDs, most normal patients can compensate for this decrease. More significant changes may occur in patients with prior renal dysfunction or reduced perfusion. These patients are less likely to be able to tolerate the decrease in prostaglandin synthesis and are at greatest risk for side effects. Although renal events are uncommon, they can have profound consequences if the drug use is not stopped and appropriate care is not initiated.

The effect of NSAIDs on the function of antihypertensive medications is another area of concern. Concomitant use of NSAIDs plus antihypertensive medication increases with age to greater than 50% among the elderly.¹⁰ A large, case-controlled study of patients more than 65 years of age demonstrated that recent users of NSAIDs had a 1.7-fold increase in risk of initiating antihypertensive therapy when compared with non-NSAID users.¹¹ It appears that NSAID use reduces the antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitors to the greatest degree while having lesser effects on beta blockers, diuretics, vasodilators, and calcium channel blockers.^12,13

Allergy to NSAIDs occurs in approximately 0.3% of the population. Manifestations of this allergy include angioedema, urticaria, and asthma, especially associated with nasal polyposis. Patients may describe certain side effects to NSAIDs as allergies. For example, some patients refer to dyspepsia or peptic ulcer disease as an allergy rather than as an adverse reaction. In reviewing the patient history, it is prudent to clarify this point.

One might generalize that the patient who is allergic to one NSAID is allergic to all NSAIDs, and this assumption is generally true. However, some patients clearly are allergic to one product and are able to tolerate another without any apparent adverse reaction. The use of the second NSAID is at times initiated by a physician who does not realize the past history of side effects or by the patient when an over-the-counter medication was selected. Therefore, the physician confronted with a patient with a legitimate aspirin allergy who is truly in need of a nonsteroidal agent to control an inflammatory process might cautiously prescribe a non-acetylated salicylate, such as salicylate or choline magnesium trisalicylate.

A not uncommon side effect associated with NSAIDs is interference with hemostatic disorders. Both PGI₂ and TXA₂ are necessary for the regulation of platelet function and homeostasis. They are synthesized by prostacyclin and thromboxane synthase, and each has opposing actions on blood vessels and platelets. Aspirin irreversibly acetylates cyclooxygenase and thereby inhibits synthesis of both TXA₂ and PGI₂. In contrast, NSAIDs reversibly inhibit cyclooxygenase. There is conflicting evidence as to whether aspirin and other NSAIDs are associated with increased bleeding from surgery.¹⁴ However, where an association is suspected, the following factors may portend a high risk for bleeding complications: age older than 60 years, bleeding disorders (eg, von Willebrand’s disease or hemophilia), liver dysfunction, thrombocytopenia, and other risk factors such as alcohol use and use of oral anticoagulants. The newer COX-2 selective agents such as celecoxib and rofecoxib do not significantly interfere with platelet function.

Prevention of Complications

When possible, a more COX-2 selective NSAID is preferred. Drugs that do not significantly inhibit cyclooxygenase in the stomach appear to be less likely to cause GI ulceration.¹⁵ Patients are instructed to refrain from taking two or more NSAIDs at the same time, to have food when these medications are taken, to be aware of the side effects of these drugs, and to report symptoms promptly. Patients also should be instructed that serious side effects might not cause symptoms. Since patients may have a GI bleed as the first manifestation of peptic ulceration associated with NSAIDs, the development of more highly selective COX-2 agents may offer increased safety margins. New products have been developed that are more highly COX-2 selective than those currently available and that appear to minimize gastric mucosal damage. Some of the relatively COX-2 selective NSAIDs that are currently available, such as etodolac, are associated with less gastric injury when prescribed at therapeutic doses used to treat osteoarthritis. The newer COX-2 selective agents such as celecoxib and rofecoxib may be safer.^15,16

Physicians need to be aware of common potential complications of NSAIDs and respond adequately should these occur. Caution in prescribing NSAIDs is particularly recommended in circumstances in which long-term use of these drugs is being considered and in those in which the patient is elderly.

NSAID use over the short term presents fewer risks. Even so, although concern about side effects is reduced, the physician should not omit a review of potential adverse reactions with the patient.

Physician asked to "clear" patients for surgery, the safest approach to the patient who is taking an NSAID is to stop the agent prior to the commencement of an invasive procedure. A common rule of thumb used is to discontinue the NSAID five half-lives of the drug prior to the procedure. Aspirin, which irreversibly acetylates platelets, should be discontinued 10 to 14 days prior to the surgery so that new platelets can be produced. With the more selective COX-2 inhibitors, this should not be necessary.

Non-NSAIDs to Manage Acute Pain

Opioids

Acetaminophen

Acetaminophen reduces pain and is an antipyretic. It inhibits prostaglandin synthesis in the central nervous system but does not affect prostaglandin synthesis in the periphery and has minimal, if any, effect on inflammation in the periphery. Excessive use of acetaminophen, especially in those who drink alcohol excessively, may be associated with liver toxicity.¹⁷ Therefore, a cautious approach is needed for such individuals wishing to use this medicine.

Antidepressants

Tricyclic antidepressants have been used as an adjunct in decreasing pain perception. Their toxicity is usually not a major factor; the primary side effects are dry mouth, blurred vision, constipation, potential cardiac arrhythmia, and somnolence.¹⁸ The newer antidepressant medicines, including selective serotonin reuptake inhibitors, may also be effective but seemingly less so than the tricyclic drugs. Anticonvulsant medicines may be helpful when nerve injuries are associated with pain since these medications reduce neuronal hyperexcitability.

New Agents

New agents for the control of pain include topical agents that take advantage of the accumulation of substance T at sites of pain. Capsaicin, a naturally occurring substance derived from plants, can be applied as a cream or liquid roll-on and may be useful in certain types of pain, such as posttherapetic neuralgia and diabetic neuropathy.¹⁹ Clinical experience suggests that it is a useful therapy for some patients with fibromyalgia. This product can induce local irritation with a sense of burning, and one should be cautious about placing any of the products on either the conjunctiva or other mucous membranes.

Tramadol hydrochloride blocks reuptake of both norepinephrine and serotonin, as do the tricyclic antidepressants, and binds to opioid receptors, as do opioid analgesics, albeit more weakly. The combination of these two known pain-relieving mechanisms makes this an attractive drug. Side effects of tramadol include constipation, nausea, and vomiting and are similar to the side effects of opioids. Seizures may also occur.²⁰

Conclusions

The use of NSAIDs for the control of acute pain is clearly an attractive alternative to other available products. NSAIDs offer a combination of safety and efficacy. In my own clinical practice, I do not obtain laboratory tests with use of less than three to four weeks unless clinically indicated. If a patient has a complaint following the institution of therapy, appropriate intervention and evaluation are always performed.

NSAIDs that have a short half-life and a rapid onset of action are usually considered the safest of these agents because the time they reside in the body is limited (Table). The potential for adverse reaction is thereby decreased and, should one occur, the time the patient is exposed to the drug is shorter than that with other drugs. Such drugs are especially attractive for people with gastrointestinal or renal dysfunction and for the elderly.