Recommendations for Management
From both the patient's and the physician's perspectives, the problem lies in balancing the risks and benefits of medications for pain relief. Of course, this is not unique to these medications, but their use highlights the issues to be considered. Below are several questions that should be considered when one makes treatment decisions about pain medications in patients with or at high risk for cardiovascular disease. A suggested stepped-care approach to management of patients with musculoskeletal symptoms is shown in Figure 7 in the original guideline document and discussed in detail below.
What Are the Treatment Considerations?
Musculoskeletal symptoms should be categorized as those that result from tendonitis/bursitis, those that result from degenerative joint problems (e.g., osteoarthritis), or those that result from inflammatory joint problems (e.g., rheumatoid arthritis). Initial treatment should focus on nonpharmacological approaches (e.g., physical therapy, heat/cold, orthotics).
For patients whose symptoms are not controlled by nonpharmacological approaches, pharmacological treatments should then be considered. When choosing any medication, both safety and efficacy should be considered. In general, the least risky medication should be tried first, with escalation only if the first medication is ineffective. In practice, this usually means starting with acetaminophen or aspirin at the lowest efficacious dose, especially for short-term needs. Despite the potential for abuse, a role remains for narcotic medications for short-term pain relief. It should be recognized that with the exception of aspirin, the "low-risk" medications mentioned above have not been subjected to randomized clinical trials to conclusively demonstrate their superior safety.
In patients who do not tolerate these simple interventions or who require long-term or high-dose therapy, the issues become more complex. Long-term or high-dose therapy with aspirin and other nonsteroidal antiinflammatory drugs (NSAIDs) is associated with increased risk for gastrointestinal (GI) bleeding. Occasionally, high-dose acetaminophen can result in hepatic toxicity, especially in patients who consume excess alcohol. When acetaminophen, aspirin, and perhaps even narcotic medications (for acute pain) are not effective, tolerated, or appropriate, it may be reasonable to consider an NSAID as the next step; however, this should be coupled with the realization that effective pain relief may come at the cost of a small but real increase in risk for cardiovascular or cerebrovascular complications (see Figure 7 in the original guideline document).
The scientific evidence to date (see the Table in the original guideline document titled "NonSelective NSAIDs and Cardiovascular [CV] Risk") indicates that important differences exist between these agents in terms of risk of major thrombotic events. Clinicians are cautioned against relying on meta-analyses that involve an incomplete set of trials, contain small numbers of events, and focus only on short-term follow-up when assessing the relative risks of various agents. Naproxen appears to be the preferred choice.
What Patient Characteristics Should Be Considered?
Patients with a history of or risk for GI bleeding, especially in relation to aspirin or other nonspecific NSAID use, might be given acetaminophen initially. Alternatively, proton-pump inhibitors may diminish the risk of recurrent GI bleeding in subjects who require low-dose aspirin. If these alternatives are not possible, it may be reasonable to consider a cyclooxygenase (COX)-2 inhibitor if the potential benefits of treatment are believed to outweigh the potential cardiovascular risks. Patients who are tolerant of nonspecific NSAIDs but find them insufficient could also consider a COX-2 inhibitor.
Patients with or at risk for active atherosclerotic processes, including those with recent bypass surgery, unstable angina or myocardial infarction, or ischemic cerebrovascular events, have greater increases in absolute risk for adverse cardiovascular effects when given a COX inhibitor. (It is difficult to provide precise estimates of the absolute increase in risk because the excess number of events is related to such factors as the underlying risk of the patient, the relative risk of the drug, and the duration of follow-up). In these patients, prudence dictates extra caution in the use of COX-2 inhibitors, which should include the use of only the recommended doses and for the shortest period of time required to control symptoms. Every effort should be made to assess and treat modifiable risk factors before and during NSAID treatment. COX inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure, which may contribute to their adverse cardiovascular effects. Renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors. This is especially true when these drugs are given to subjects with preexisting hypertension, renal disease, and heart failure (see Figure 7 in the original guideline document).
If You Use a COX-2 Inhibitor, Does Selectivity Matter?
The available data have implicated several COX-2 inhibitors with varying degrees of selectivity. As suggested by the data summarized in the Table, Figure 1, and Figure 6 of the original guideline document, even a relative lack of COX-2 selectivity does not completely eliminate the risk of cardiovascular events, and in that regard, all drugs in the NSAID spectrum should only be prescribed after thorough consideration of the risk/benefit balance. Additional data bearing on this issue will be provided in the ongoing PRECISION trial (Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen or Naproxen; http://www.clinicaltrials.gov, No. NCT00346216), which is randomizing patients with rheumatoid arthritis or osteoarthritis to celecoxib, ibuprofen, or naproxen, the latter being 2 NSAIDs that are further toward the non-COX-2 end of the spectrum (see Figure 6 in the original guideline document).
Can Patients Using Aspirin for Cardioprotection Also Use NSAIDs or Selective COX-2 Inhibitors for Pain Relief?
Evidence indicates that ibuprofen, but not rofecoxib (a COX-2 inhibitor), acetaminophen, or diclofenac, interferes with aspirin's ability to irreversibly acetylate the platelet COX-1 enzyme, and it would be expected, although it has not been proved, that this would reduce the protective effect of aspirin on risk for atherothrombotic events. Per an U.S. Food and Drug Administration (FDA) advisory:
"Patients taking immediate release low-dose aspirin (not enteric coated) and ibuprofen 400 mg should take the ibuprofen at least 30 minutes after aspirin ingestion, or at least 8 hours before aspirin ingestion to avoid any potential interaction. . . . Recommendations about concomitant use of ibuprofen and enteric-coated low dose aspirin cannot be made based on available data. One study showed that the antiplatelet effect of enteric-coated low dose aspirin is attenuated when ibuprofen 400 mg is dosed 2, 7, and 12 hours after aspirin."
Of note, the combination of aspirin (necessary for protection against cardiovascular events) and a coxib may ameliorate the gastric mucosal protective effect of COX-2 inhibition. The combination of the two may also prolong the time for recovery from gastric mucosal injury.
