The concurrent use of opioids, NSAIDs, and acetaminophen often provides more analgesia than does either of the drug classes alone.
The addition of NSAIDs and acetaminophen to opioid analgesics may achieve a "dose-sparing" effect such that lower doses of opioids may now produce pain relief with fewer side effects (Hodsman, Burns, Blyth, et al., 1987; Weingart, Sorkness, and Earhart, 1985).
In contrast to opioids, NSAIDs do not produce tolerance, physical, or psychological dependence, they are antipyretic, and have a different spectrum of toxicity. Used as single agents, NSAIDs have a ceiling effect on their analgesic potential, so the use of doses higher than specified in the package insert is not recommended.
The nonacetylated salicylates such as salsalate, sodium salicylate, and choline magnesium trisalicylate do not affect platelet aggregation profoundly and do not alter bleeding time (Estes and Kaplan, 1980; Danesh, Saniabadi, Russell, et al., 1987; Day, Furst, Graham, et al., 1987; Morris, Sherman, McQuain, et al., 1985; Stuart and Pisko, 1981; Zucker and Rothwell, 1978). Aspirin, the prototype of the acetylated salicylate, produces an irreversible inhibition of platelet aggregation, which may prolong bleeding time for up to several days after ingestion (Stuart, Murphy, Oski, et al., 1972; Sutor, Bowie, and Owen, 1971; Weiss, Aledont, and Kochwa, 1968). The nonacetylated salicylates, such as sodium salicylate and choline magnesium trisalicylate, have minimal effects on platelet aggregation and do not appear to alter bleeding time clinically (Day, Furst, Graham, et al., 1987; Morris, Sherman, McQuain, et al., 1985; Stuart and Pisko, 1981; Zucker and Rothwell, 1978). Other NSAIDS produce a reversible inhibition of platelet aggregation, which persists while the drug is in the systematic circulation (Schlegel, 1987). Therefore, with the exception of the nonacetylated salicylates noted above, NSAIDs should be avoided if possible in patients who are thrombocytopenic or who have a clotting impairment.
NSAIDs bind extensively to plasma proteins and therefore may be displaced by or may displace other protein-bound drugs such as coumadin, methotrexate, digoxin, cyclosporine, oral antidiabetic agents, and sulfa drugs. Such interaction may enhance therapeutic or toxic effects of either drug. The use of NSAIDs has been associated with both minor (dyspepsia, heartburn, nausea, vomiting, anorexia, diarrhea, constipation, flatulence, bloating, epigastric pain, and abdominal pain) and major (bleeding, ulceration, and perforation) GI toxicities. Serious effects are not always preceded by minor GI effects; patients should be advised to report any GI disturbances.
Hepatic and renal dysfunction or toxicity, which can occur at any time in the course of NSAID therapy, are of particular concern during long-term use (Sunshine and Olson, 1989). The risk of renal dysfunction is greatest in patients with advanced age, preexisting renal impairment, heart failure, hepatic dysfunction, hypovolemia, concomitant therapy with other nephrotoxic drugs such as diuretics, or elevated levels of angiotensin II or catecholamines. Antipyretic and anti-inflammatory effects of NSAIDs may mask the usual signs and symptoms of infections.
Adverse effects of NSAIDs that may appear at any time:
Even though NSAIDs are effective in relieving mild pain and are opioid sparing for moderate to severe pain, patients who take them, especially if elderly, should be monitored carefully for adverse effects.
Most NSAIDs are available as oral tablets, caplets, or capsules, and several are available as oral liquids. Rectal suppositories of aspirin, acetaminophen, and other NSAIDs are commercially available or can be compounded easily by pharmacists. Ketorolac tromethamine is the only NSAID that is currently available for short-term parenteral administration. Table 9 provides dosing data for acetaminophen and NSAIDs.
It is impossible to predict which NSAID will be best tolerated by a particular patient; no particular NSAID has demonstrated superiority over others for pain relief. Once an NSAID has been selected, the dose should be increased until pain has been relieved or the maximal tolerated dose has been achieved. The duration of analgesia does not always correlate with the serum half-life of the NSAID. Therefore, the response of the patient should guide the clinician in selecting dosing intervals of these agents. Because NSAIDs and adjutant analgesics have ceiling effects to their efficacy, if a patient does not respond to the maximal dose of one NSAID, another should be tried before discontinuation of NSAID therapy. The initial choice of NSAID should be based on the efficacy, safety, and relative expense; generally, the least expensive NSAID should be chosen.
The WHO Ladder
Figure 2: The WHO Ladder
Dosing Data for Acetaminophen (APAP) and NSAIDs
Figure 5: Pain Management Plan