Nonopioid Therapy

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Acetaminophen

Mechanism of Action

Acetaminophen acts by inhibiting prostaglandin synthesis in the central nervous system, resulting in an analgesic and antipyretic effect similar to that seen with aspirin therapy. Unlike aspirin, however, acetaminophen is a weak prostaglandin inhibitor in the periphery and possesses no significant anti-inflammatory properties (18).

There is some early evidence that acetaminophen may act by inhibiting a variant of the enzyme cyclooxygenase, which researchers have labeled cyclooxygenase-3 (COX-3) (19,20). The COX enzyme seems to be involved in the synthesis of prostaglandins, which play many roles throughout the body, including mediation of pain and inflammation. As discussed in the NSAID section of this chapter, researchers discovered at least two variations of the COX enzyme, COX-1 and COX-2. The COX-3 enzyme has now been isolated, and it is postulated that its activity may be inhibited by acetaminophen. Inhibition of the newly discovered COX-3 isoenzyme appears to result in analgesic and antipyretic effects; this result is consistent with the clinical effects seen with acetaminophen therapy. Additional research in the future will confirm the existence of the COX-3 enzyme and the role acetaminophen plays in its inhibition.

Place in Therapy

Acetaminophen may be administered as monotherapy for the treatment of mild pain or in combination with other nonopioids such as aspirin, caffeine, salicylamide, and others. Results of studies that evaluated pain relief from these acetaminophen and nonopioid combination products have been conflicting. Acetaminophen combined with aspirin and caffeine may be more effective than acetaminophen alone in the treatment of tension headaches, but acetaminophen combined with aspirin, caffeine, or salicylamide generally has not been shown to be more effective than optimized dosages of acetaminophen alone, and combination therapy has not been shown to cause fewer adverse effects (21). Acetaminophen (650-mg doses) in combination with an opioid (i.e., codeine, oxycodone) may be used to treat moderate pain because the therapeutic effect shown from combination therapy exceeds that of either analgesic alone or that achieved by increasing the opioid dose (21).

Acetaminophen is usually the drug of choice for the treatment of mild-to-moderate pain in older adults because of its low cost, therapeutic efficacy, and safety profile. The American Medical Directors Association (AMDA) Clinical Practice Guidelines, "Chronic Pain Management in the Long-Term Care Setting," recommend the use of acetaminophen as a first-line analgesic for older adults if they do not have liver disease or consume alcohol (22). The American Geriatrics Society (AGS) provided the guidelines, "The Management of Persistent Pain in Older Persons," in 2002, advocating the treatment of mild-to-moderate musculoskeletal pain with around-the-clock doses of acetaminophen and with dosage reduction in patients with organ dysfunction or hazardous or harmful alcohol use (23).

Osteoarthritis (OA) is a painful disorder that is highly prevalent in older adults. Amadio and Cummings evaluated acetaminophen 4000 mg per day vs placebo in 25 patients with OA of the knee (24). Acetaminophen resulted in significant improvements in pain at rest and on motion and on physician and patient global assessment. Bradley et al. demonstrated equivalent pain relief with acetaminophen 4000 mg per day compared to ibuprofen 2400 mg per day; however, joint inflammation was more responsive to ibuprofen than acetaminophen (25). Williams et al. compared acetaminophen 2600 mg per day vs naproxen 750 mg per day in 178 patients with OA of the knee (26). The authors concluded that the two regimens had similar efficacy, although it was slightly better for naproxen. Additional clinical trials have demonstrated superior efficacy of traditional NSAID therapy compared to acetaminophen (27-29).

Geba et al. evaluated the efficacy of rofecoxib (12.5 and 25 mg/day), celecoxib (200 mg/day), and acetaminophen (4000 mg/day) in the treat ment of OA of the knee (30). The authors concluded that the three NSAID regimens had superior efficacy vs that for acetaminophen-treated patients. For the rofecoxib arms, the differences were statistically significant. A critique of this article pointed out that it would have been useful to compare these newer COX-2 enzyme selective inhibitors with traditional NSAIDs (e.g., ibuprofen, naproxen), which have demonstrated similar effectiveness compared to rofecoxib in OA (31). The reviewer further observed that only one of six patients discontinued acetaminophen therapy owing to lack of efficacy.

Therefore, using acetaminophen as first-line therapy is still reasonable as it is less expensive, is efficacious, and causes fewer adverse effects than NSAID agents. The American College of Rheumatology also recommended acetaminophen as an initial intervention for mild-to-moderate OA joint pain (32). The American Pain Society (APS) recommended acetaminophen as the analgesic of choice for mild OA pain and as continued therapy for patients who experience a favorable risk-to-benefit ratio (33).

Adverse Effects and Precautions

Acetaminophen is usually well tolerated and has no common adverse effects when used in therapeutic doses of no more than 4000 mg per day (34). Patients receiving acetaminophen in the trials described in the section on its place in therapy experienced no serious drug-related adverse effects (35). Bannwarth and colleagues evaluated both single- and multiple-dose pharmacokinetics of acetaminophen in polymedicated very old patients with rheumatic pain (36). Patients were 89 ┬▒4 years of age and taking three to eight concomitant medications. Pharmacokinetic parameters were derived from a single dose of 1000 mg acetaminophen and after receiving 1000 mg three times daily for 5 consecutive days. The investigators observed no drug accumulation with multiple doses of acetaminophen compared to single doses and concluded that 1000 mg three times daily is safe for older adults.

Some studies suggested that chronic ingestion of acetaminophen increases the risk of chronic renal disease (37). Perneger et al. concluded that patients taking an average of more than one acetaminophen tablet per day or a cumulative acetaminophen intake of more than 1000 tablets per lifetime doubled the odds of developing end-stage renal disease (38). Despite these data, the Scientific Advisory Committee of the National Kidney Foundation recommended that acetaminophen be used as the analgesic of choice in patients with impaired renal function (39,40).

Hepatic toxicity rarely occurs with daily acetaminophen doses of 4000 mg per day or less; however, higher daily doses taken chronically or concurrent ethanol consumption increases the risk of acetaminophen-induced hepatotoxicity (1,41,42). Patients and prescribers alike need to be mindful of the ubiquitous nature of acetaminophen in multiple-ingredient prescription and nonprescription medications. For example, Vicodin ES (extra strength) caplets contain 7.5 mg hydrocodone and 750 mg acetaminophen. If a patient consumed two caplets very 4 hours around the clock, this would result in a total daily acetaminophen dose of 9000 mg. Similarly, many multisymptom-relieving nonprescription products contain acetaminophen. Cham and colleagues surveyed 213 subjects who presented in the emergency department on their basic knowledge about nonprescription analgesics (43). Of the respondents, 64% did not know acetaminophen use may result in liver toxicity. In September 2002, the Nonprescription Drugs Advisory Committee of the Food and Drug Administration (FDA) suggested that acetaminophen labeling should be changed to include a liver damage warning separate from the current alcohol warning (44).

Appropriate use of acetaminophen by older adults with normal renal and hepatic function and no history of alcohol abuse is to limit the total daily dose to 4000 mg per day. The AGS guidelines recommended acetaminophen dosage reduction by 50-75% or selection of alternate therapy in patients with organ dysfunction or hazardous or harmful alcohol use (23).

Although acetaminophen does not affect platelet function, it may cause elevation of the prothrombin time in warfarin-treated patients, especially with higher doses of each drug (45).

Summary

In summary, acetaminophen is an effective analgesic for mild-to -moderate pain in older adults. Although acetaminophen will treat the pain associated with inflammatory disease states, it will not noticeably reduce inflammation. Close attention should be paid not to exceed the recommended 4000 mg per day. Patients at risk for acetaminophen use, such as those who use alcohol or have liver disease, should not receive acetaminophen.

Nonsteroidal Anti-Inflammatory Drugs

Mechanism of Action

NSAIDs are one of the most widely prescribed groups of medications worldwide. NSAIDs exhibit the same antipyretic and analgesic activity seen with acetaminophen, but also exhibit anti-inflammatory properties. Many painful conditions that affect older adults, particularly arthritis (rheumatoid arthritis [RA] more so than OA), have an inflammatory component. The NSAIDs also reduce swelling, tenderness, and stiffness, allowing for improved overall physical functioning (46). Up to 25% of ambulatory older adults use prescription-strength NSAIDs each year; an even greater percentage of older adults may actually be using NSAIDs regularly if nonprescription strength NSAIDs are also considered (47).

NSAIDs act by inhibiting the synthesis of prostaglandins. Arachidonic acid is the primary precursor of prostaglandins and is metabolized by either the lipoxygenase pathway to leukotrienes or the COX pathway to prostaglandins, thromboxanes, and prostacyclins. Two COX isoforms have been identified, COX-1 and COX-2. COX-1 is found in most normal cells and tissues and is considered homeostatic in function; COX-2 is induced in inflammatory settings by cytokines and inflammatory mediators. COX-2 is also constitutively expressed in certain areas of the kidney and brain. COX-1 leads to the production of prostaglandins and thromboxanes responsible for GI mucosal integrity, platelet aggregation, and renal function. COX-2 leads to the production of prostaglandins responsible for inflammation and other functions such as mitogenesis and growth, regulation of female reproduction, bone formation, and renal function (48,49).

Older NSAIDs such as aspirin, ibuprofen, naproxen, and others are nonselective inhibitors of the two isoforms of the COX enzyme (e.g., they inhibit both COX-1 and COX-2 isoenzymes). Not surprisingly, the adverse effects associated with nonselective NSAID therapy are an extension of the pharmacological effect; these effects include dyspepsia, epigastric distress, nausea, erosion or ulceration of the GI mucosa, inhibition of platelet aggregation and prolonged bleeding time, deterioration of renal function, overt renal decompensation, and acute tubular necrosis with renal failure (50).

Newer NSAIDs (such as rofecoxib, celecoxib, and valdecoxib) with greater selectivity for COX-2 than COX-1 have been developed to treat pain and inflammation with fewer adverse effects than nonselective NSAIDs. These agents have the analgesic, anti-inflammatory, and antipyretic activities of nonspecific NSAIDs, but lack antiplatelet activity, do not affect bleeding time, and are less toxic to the GI system.

Place in Therapy

NSAIDs play a major role in the management of acute and chronic pain experienced by older adults, especially syndromes with an inflammatory component. NSAIDs reduce joint pain and stiffness of both OA and RA and tenderness and swelling associated with RA. NSAIDs are also effective at reducing pain in acute gout, bursitis, tendonitis, seronegative spondyloarthropathies, and soft tissue injuries and postsurgical pain (47).

The Agency for Health Care Policy and Research (AHCPR) 1992 guidelines, "Acute Pain Management: Operative or Medical Procedures and Trauma," recommended that the pharmacological management of mild-to-moderate postoperative pain should begin with NSAID therapy unless there is a contraindication (51). Furthermore, the guidelines advocated the use of NSAIDs alone after relatively noninvasive surgery. If NSAID therapy alone is insufficient, it is reasonable to administer a NSAID along with an opioid, resulting in an "opioid-sparing" effect and reducing opioid side effects. The concurrent use of opioids and NSAIDs often provides more effective analgesia than either of the drug classes alone (51).

Ketorolac (Toradol) is a nonselective NSAID, and is the first NSAID available in the United States for parenteral administration. This agent is useful in acute pain situations (such as related to trauma or surgery) when oral analgesic therapy is not feasible. Ketorolac has even been used pre-operatively as a preemptive analgesic with good results (52). It is reasonable to expect that an injectable COX-2-specific NSAID will be available soon, which would be expected to reduce the risk of bleeding when administered to preempt or treat surgical pain. NSAIDs have also been useful in treating acute pain from gall bladder and urinary tract spasms, for which opioids may have relatively less effect (53).

Several studies have compared the analgesic efficacy of the nonselective NSAIDs and the COX-2-specific NSAIDs in the management of acute pain. A review of six randomized controlled trials compared the efficacy of rofecoxib to maximal recommended doses of nonselective NSAIDs (naproxen 550 mg or ibuprofen 400 mg) in treating postoperative dental pain (54). Total pain relief over the 9-hour postoperative period was similar for 50 mg rofecoxib and the maximal analgesic doses of the nonselective NSAIDs. Another study evaluated the analgesic efficacy of rofecoxib 50 mg vs ibuprofen 400 mg in the treatment of acute dental pain (55). Although there was no difference in the level of analge sia achieved, patients who received rofecoxib maintained analgesia for a significantly longer period.

NSAID agents have been effective in the treatment of mild-to-moderate chronic pain, particularly for those conditions associated with inflammation. The majority of prescriptions written for NSAID therapy in older adults are for the treatment of arthritis pain or inflammation. Historically OA was not considered an inflammatory process until the disease reached an advanced stage; however, others have suggested that OA may be associated with local low-grade inflammation (56-58). The guidelines developed by the APS for the management of pain in OA do not acknowledge the superiority of NSAIDs (selective or nonselective) compared to acetaminophen for OA pain relief (33). Guideline recommendations are to use a COX-2-selective NSAID for patients with moderate-to-severe pain or inflammation as the first analgesic choice and for patients who have not received relief with acetaminophen 4000 mg per day unless the patient is at significant risk for hypertension or renal disorder (use any NSAID cautiously in these situations). Nonselective NSAIDs should only be considered if the patient is not responsive to or not able to take COX-2-selective NSAIDs or acetaminophen up to 4000 mg per day and may require cytoprotective therapy (i.e., misoprostol or a proton pump inhibitor [PPI]) if the patient is at high risk for gastrotoxicity.

The APS guidelines for the treatment of pain in RA are very similar to those for OA. Drugs that are disease-modifying agents in RA that also reduce pain are considered the drugs of choice. However, COX-2-selec-tive NSAIDs should be used if additional analgesic or anti-inflammatory agents are needed; the same precautions and provisions listed above should be followed.

The AGS guidelines for the treatment of persistent pain in older adults also recommended use of NSAID therapy when maximum safe doses of acetaminophen do not adequately control pain (23). The AGS guidelines further recommended that patients who are appropriate candidates for NSAID therapy and require daily therapy should be started on a COX-2-selective NSAID preferentially. Nonacetylated salicylates such as choline magnesium trisalicylate or salsalate are relatively safe and less-expensive treatment options.

Adverse Effects and Precautions

As a class, clearance of NSAID agents from the body differs for younger and older patients (47). Most NSAIDs undergo both Phase I

(oxidation or reduction) and Phase II (glucuronidation or acetylation) metabolism. Phase I metabolism may be reduced in older adults, and deteriorating renal function may prolong exposure to NSAIDs excreted by the kidneys (47). NSAID toxicity is generally considered dose related; therefore, it is prudent to start at a low dose and increase slowly and only as needed.

NSAIDs reduce pain and inflammation by inhibiting the formation of prostaglandins. However, this is also the mechanism for most of the toxicities, particularly GI and renal, associated with NSAID therapy.

Gastrointestinal Toxicity

NSAID agents cause a host of GI toxicities, ranging from dyspepsia, nausea, and diarrhea to mucosal damage such as GI erosions, ulcers, perforations, obstructions, and serious bleeding. NSAIDs are responsible for significant morbidity and mortality in the United States, with up to 100,000 hospitalizations and 16,000 deaths per year (59,60). The decision to begin a patient on NSAID therapy should reflect careful consideration.

Up to 30% of patients complain of dyspepsia on NSAID therapy; this may be intolerable (47). The mechanism leading to this complaint is not clear, and the development of dyspepsia does not correlate with GI mucosal damage (60,61). Therapeutic options include decreasing the NSAID dose, switching to a different NSAID agent, adding cytoprotective therapy (such as a PPI), or discontinuing NSAID therapy.

certainly more worrisome is the development of gastric erosions, perforations, obstructions, and major GI bleeding secondary to NSAID therapy. Approximately 15-30% of NSAID users will show endoscopic evidence of a gastric or duodenal ulcer (61). The more serious GI events, such as perforation, obstruction, or major GI bleeding, occur in approx 2% of patients treated with NSAIDs over a 1-year period (47). Risk factors include prior history of a clinical GI event (such as perforation, ulcer, or GI bleed), advanced age, concomitant warfarin or corticosteroid therapy, use of high-dose or multiple NSAIDs, and significant comorbidity (47).

The incidence and severity of these complications illustrate the importance of careful prospective consideration of the appropriateness of a patient for NSAID therapy. Other therapeutic options include concurrent cytoprotective therapy with either misoprostol (a prostaglandin analog) or an antisecretory agent (H2 antagonist or PPI) or use of a COX-2-spe-cific NSAID in lieu of a nonspecific NSAID agent.

Several studies have evaluated the efficacy of concomitant therapies in preventing NSAID-induced mucosal injury. Sucralfate has not shown any benefit in preventing gastric ulcers in NSAID-treated patients with OA (62).

Concurrent treatment with an H2 receptor antagonist prevented NSAID-induced duodenal ulcers, but was less effective in preventing gastric ulcers (63,64). Yeomans et al. demonstrated that omeprazole, a PPI, was more effective than H2 receptor antagonists in preventing recurrence of gastroduodenal ulcers (65).

Misoprostol is the only therapy indicated for the prevention of NSAID-related GI complications. An oral prostaglandin Ej (PGEX) analog, misoprostol is an antisecretory agent with protective effects on the gastroduodenal mucosa. Silverstein et al. conducted the Misoprostol Ulcer Complication Outcomes Safety Assessment (MUCOSA) study (66). Concurrent NSAID and misoprostol therapy (200 |g four times daily) resulted in 40% reduction of the overall rate of complicated upper GI events. Misoprostol frequently causes adverse events that can limit therapy in the elderly, such as abdominal pain, heartburn, and diarrhea. Less-frequent dosing (such as 200 |g twice daily) results in fewer adverse effects, but research has shown that misoprostol must be taken at least three times daily to effectively prevent NSAID-induced gastric ulcers (67).

Misoprostol has been compared to omeprazole in the healing and prevention of ulcers associated with NSAIDs (68). Results showed that healing rates in patients with duodenal ulcer were higher in the omeprazole-treated patients, but healing rates in patients with erosions alone were higher with misoprostol. More patients remained ulcer free when maintained on omeprazole vs misoprostol, and omeprazole was better tolerated throughout the study.

The COX-2-specific NSAID agents, compared to nonselective NSAIDs, decreased both endoscopically visualized ulcers and clinically important GI events, with a relative risk reduction of 50-65% (69). Large studies that compared rofecoxib 50 mg four times a day (vs naproxen 500 mg twice daily) (70) and celecoxib 400 mg twice daily (vs diclofenac or ibuprofen) (71) showed two to three times fewer symptomatic ulcers and ulcer complications with COX-2 therapy. In the Celecoxib Long-Term Arthritis Safety Study (CLASS), however, the GI ulceration rate increased when the patients were also taking aspirin for cardiovascular prophylaxis (71). It remains to be determined what impact low-dose aspi rin will have on COX-2 therapy, possibly negating or reducing the GI benefits of the coxib (COX-2 inhibitor) (47).

Given that two strategies used to reduce the risk of NSAID-induced GI toxicities are to add a PPI to nonselective NSAID therapy or to use a COX-2-specific NSAID, it seems reasonable to compare these two strategies in terms of GI outcomes. Chan and colleagues evaluated celecoxib 200 mg twice daily vs diclofenac 75 mg twice daily plus omeprazole 20 mg for a 6-month period in patients who had used NSAIDs for arthritis and experienced ulcer bleeding (72). The results showed similar therapeutic outcomes and a similar rate of recurrent bleeding (4.9% of celecoxib-treated patients; 6.4% of patients treated with diclofenac and omeprazole). Given similar therapeutic and toxic outcomes, the question of whether to use a nonselective NSAID with PPI or misoprostol cotherapy vs a COX-2-specific NSAID largely becomes one of economics and tablet burden. In this case, monotherapy with the COX-2-specific NSAID is less costly than combination therapy (nonselective NSAID plus PPI, for example). However, many patients continue therapy with a PPI despite switching to a COX-2-specific NSAID, negating the cost savings. In addition, as PPIs become available generically, this may render combination therapy more cost-effective. Last, the prescriber must consider the tablet burden for the patient, particularly older patients, who may find a twice-daily nonselective NSAID plus once-daily PPI more burdensome than a once-daily COX-2-specific NSAID.

Renal Toxicity, Peripheral Edema, and Hypertension

Renal toxicity occurs in approx 5% of patients taking an NSAID agent (1). Because of age-related changes and the effects of other drug therapy on renal function (e.g., diuretic-induced volume depletion), older adults may be at greater risk for renal toxicity from NSAIDs. Examples of NSAID-induced renal toxicity include acute reversible renal failure, impaired renal excretion of water and electrolyte (sodium and potassium), acute interstitial nephritis, and analgesic nephropathy (73).

Renal prostaglandins are involved in the regulation of several homeo-static functions in the kidney, including renal blood flow (particularly in individuals with decreased actual or effective intravascular volume) and sodium and potassium excretion (47). It has been shown that the COX-1 isoenzyme is expressed widely throughout the kidney, and it has now been shown that COX-2 is also expressed constitutively in the renal vasculature, glomerulus, and ascending limb of the loop of Henle (47). Con sequently, both nonselective and COX-2-specific NSAIDs have been associated with renal dysfunction (74). The APS guidelines advised that "unless data are obtained from patients who are at risk for renal complications, it would be wise to avoid COX-2 selective medications as well as nonselective NSAID therapy in patients with a creatinine clearance of less than 30 mL per minute" (33, p. 69).

Fluid retention is a more common renal manifestation of NSAID therapy (47). Although most patients are able to tolerate the enhanced retention of sodium secondary to NSAID therapy, some patients may gain weight or develop peripheral edema, hypertension, and (rarely) pulmonary edema (47). Patients at greater risk for clinical consequences of fluid retention include those with underlying renal disease, congestive heart failure, or hepatic insufficiency or patients receiving diuretics (75). Body weight for these patients should be monitored carefully, particularly after initiating or increasing NSAID therapy.

It is common to find older adults who take both an NSAID agent and an antihypertensive agent. In one study, approx 52% of elderly (over 60 years of age) had diagnosed or untreated hypertension, and 12 to 15% of elderly were receiving at least one NSAID agent and an antihypertensive agent concurrently (76). Gurwitz et al. found that older adults (older than 65 years) are 1.7-fold more likely to require initiation of an antihyperten-sive agent when also taking an NSAID agent than patients not taking an NSAID agent (77). Meta-analyses of the effect of NSAID therapy on blood pressure showed a clinically significant mean increase of 5.0 mmHg, particularly in patients with controlled hypertension (78,79). Of those nonselective NSAIDs assessed, indomethacin, naproxen, ibuprofen, and piroxicam produced the greatest increase in mean blood pressure (80,81).

COX-2-specific NSAIDs have also been associated with an increase in blood pressure (82,83). Whelton et al. specifically evaluated the effects of celecoxib 200 mg per day and rofecoxib 25 mg per day on blood pressure and edema in patients 65 years and older with systemic hypertension and OA (82). Both agents led to increased systolic blood pressure (change <20 mmHg plus absolute value >140 mmHg). The study design prohibited a legitimate comparison between agents, however, because the study dose of rofecoxib (25 mg) is not considered equianalgesic to the dosing of celecoxib (200 mg each day) (30). The article published by Whelton et al. nonetheless reported differences between the rofecoxib and celecoxib for hypertension (14.9 vs 6.9%, p < 0.01), and significant new-onset or worsening edema associated with weight gain developed in a greater percentage of patients in the rofecoxib group (7.7%) compared with the celecoxib group (4.7%) (80). Although relationships between renal effects and dosing have often been described, no studies that compared celecoxib 200 mg to the more similar 12.5 mg rofecoxib demonstrated such differences between one COX-2 and another.

Collins et al. showed that a sustained increase (over a few years) in diastolic blood pressure of 5 to 6 mmHg may be associated with a 67% increase in total stroke occurrence and a 15% increase in coronary heart disease events (83,84). In a review of NSAID-induced hypertension, Johnson suggested that is critical to determine if an older patient even requires NSAID therapy; perhaps nonpharmacological interventions or other analgesics might suffice. If the patient requires NSAID therapy, he or she should be evaluated carefully for increases in blood pressure, edema, and weight gain (84).

Cardiovascular Disease and Thrombosis

Aspirin (a strong COX-1 inhibitor) has been widely accepted as a therapeutic intervention for prevention of cardiovascular and cerebrovascular disease owing to its ability to irreversibly inhibit platelet aggregation (85). Nonselective NSAIDs reversibly inhibit platelet aggregation, but concern has arisen that COX-2-selective NSAIDs that lack COX-1 inhibition may lead to increased incidence of thrombosis in patients at risk. In the Vioxx Gastrointestinal Outcomes Research (VIGOR) trial (rofecoxib 50 mg per day vs naproxen 1000 mg per day), there was a statistically significant decrease in nonfatal myocardial infarctions in the naproxen-treated group (70). Patients in this study were not permitted to take low-dose aspirin for cardiovascular purposes; therefore, it is unclear whether this observed effect was because of cardioprotection provided by naproxen therapy or a prothrombotic effect of rofecoxib. Conclusions also cannot be drawn from the large CLASS trial, in which celecoxib was compared to nonselective NSAIDs (71). Patients in the CLASS trial were allowed to take low-dose aspirin, and the incidence of nonfatal myocar-dial infarctions was similar in the celecoxib-treated patients and the ibuprofen- or diclofenac-treated patients. Based on the questions raised by these studies, the APS has recommended that "any patient who is at risk for a cardiac event and is treated with either a nonselective NSAID or a COX-2 selective NSAID should also receive low-dose aspirin" (31, p. 70).

In addition to the concern about increased risk of GI events when COX-2-selective agents are used with low-dose aspirin, there also is concern about the deleterious effect of some traditional NSAIDs on the cardioprotection afforded by low-dose aspirin. Although the data seem to indicate that diclofenac and rofecoxib do not negate the cardioprotective effect of low-dose aspirin, ibuprofen does appear to obviate such benefits (86,87). Because data have not been reported on other COX-2 agents or any other NSAIDs, it is difficult to surmise whether the cardioprotective benefits of aspirin will be preserved.

Summary

In summary, clinicians need to consider carefully whether NSAID therapy is appropriate for any older adult given the pathogenesis of their pain and risk factors for NSAID-induced adverse effects. At equipotent doses, the efficacy of all NSAIDs (COX-2 selective or nonselective) is similar, but individual patients may respond better to one agent than another. Additional considerations when selecting an NSAID include adverse effects (particularly GI and renal), dosing frequency, patient preference, and cost. For patients at risk for gastrotoxicity, consider a COX-2-selective NSAID or a nonselective NSAID in combination with a PPI or misoprostol. Patients who take NSAID agents should be carefully monitored for adverse effects, particularly GI dyspepsia and bleeding, weight gain, fluid retention, and hypertension. Patients at risk for cardiovascular or cerebrovascular disease should receive low-dose aspirin in combination with NSAID therapy. In this setting, one may consider either diclofenac or rofecoxib until more data become available.

Tramadol

Mechanism of Action

Tramadol is an aminocyclohexanole derivative with weak opioid agonist activity. The drug has slight preference for the ^-opioid receptor, with an affinity approx 6000-fold less than that of morphine (88). Tramadol also inhibits norepinephrine and serotonin uptake (88).

Place in Therapy

Tramadol is indicated for the management of moderate-to-moderately severe pain. Tramadol may be used when patients wish to avoid or cannot tolerate opioids but nonopioids are insufficient to manage pain and may be used in combination with acetaminophen or an NSAID agent.

Tramadol may also be used when acetaminophen is insufficient, but the patient is unable to tolerate an NSAID. The efficacy of tramadol is similar to that of equianalgesic doses of codeine and hydrocodone (23).

Tramadol has demonstrated efficacy in relieving painful conditions commonly experienced by older adults, including OA pain, chronic low back pain, painful diabetic neuropathy, and fibromyalgia pain (89). Dalgin and colleagues compared tramadol to ibuprofen in the management of OA; they found a comparable decrease in pain scores (90). Patients with OA have utilized tramadol in lieu of and adjunctive to NSAID therapy with good results (91,92). The superiority of tramadol over placebo in the management of diabetic neuropathy and fibromyalgia pain may be partly because of its mechanism of action to inhibit the reuptake of serotonin and norepinephrine.

Tramadol is now also available in combination with acetaminophen (Ultracet®). This combination product is indicated for the short-term (5 days or fewer) management of acute pain. Each tablet contains 37.5 mg of tramadol, which is less than the monotherapeutic agent (Ultram®, 50 mg per tablet), and 325 mg of acetaminophen. Fricke and colleagues evaluated tramadol and acetaminophen combination tablets, hydrocodone and acetaminophen tablets, and placebo for the treatment of pain after oral surgery (93). Two tramadol and acetaminophen tablets (total dose 75 mg tramadol and 650 mg acetaminophen) were as efficacious as one hydrocodone and acetaminophen tablet (10 mg hydrocodone and 650 mg acetaminophen), with about 50% less nausea and vomiting. Both therapies were clinically superior to placebo.

Tramadol and acetaminophen have also been evaluated in adults for the management of chronic pain, including chronic nonmalignant low back pain, OA pain, or both (94). Patients received either tramadol 37.5 mg and acetaminophen 325 mg or codeine 30 mg and acetaminophen 300 mg; one to two tablets or capsules were given every 4-6 hours, not to exceed 10 tablets or capsules per day (not to exceed 8 tablets or capsules in patients 75 years or older). Pain relief was equivalent between the two groups, and adverse effects were largely comparable (higher incidence of somnolence and constipation with codeine and acetaminophen; increased number of headaches in the tramadol and acetaminophen group).

Prescribers should be careful to limit total daily acetaminophen dosage to 4000 mg per day when using this combination analgesic. The combination may be particularly useful for older adults because less tramadol is administered per tablet, thereby reducing the likelihood of adverse effects.

The AMDA suggested that tramadol may be added to acetaminophen or an NSAID or administered as monotherapy to manage chronic pain in the long-term care setting when patients or their advocates wish to avoid opioids (22). The APS and the American College of Rheumatology have suggested similar use of tramadol for the treatment of OA pain (32,33).

Adverse Effects and Precautions

Tramadol is not a controlled substance and generally has low abuse potential in people without a previous history of substance abuse (not recommended for this population) (95).

The most common adverse effects of tramadol include dizziness, sedation, seizures, nausea, vomiting, and constipation (84). Ruoff demonstrated that a slow initial titration of tramadol improves tolerability and reduces the discontinuation rate owing to nausea, vomiting, dizziness, or vertigo (96). Tramadol was titrated to 200 mg per day in 1 day, 4 days, or 10 days. Patients with the 10-day titration rate (increased by 50 mg every 3 days to a total of 200 mg per day) had the fewest discontinuations.

Seizures have been reported with tramadol therapy (97). Risk factors for seizures include dosages above the recommended range, concurrent therapy with certain medications (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors, opioids), or use in patients with a history of seizures (89).

Tramadol can be administered as needed for relief every 4 to 6 hours, not to exceed 400 mg per day. For patients older than 75 years, not more than 300 mg per day in divided doses is recommended. For all patients with a creatinine clearance less than 30 mL per minute, it is recommended that the dosing interval be increased to 12 hours, with a maximum daily dose of 200 mg. The recommended dose for patients with cirrhosis is 50 mg every 12 hours (98). The tramadol and acetaminophen combination (Ultracet) is administered in doses of two tablets every 4 to 6 hours, to a maximum daily dosage of eight tablets. For patients with a creatinine clearance less than 30 mL per minute, it is recommended that the dosing interval be increased not to exceed two tablets every 12 hours.

Summary

Tramadol is an effective analgesic for moderate pain; it may be used after acetaminophen or NSAID failure or in combination with acetaminophen or NSAID. It is an option prior to opioid therapy, but for patients whose pain exceeds the analgesia provided by tramadol, opioid therapy should be strongly considered.

Prescribers should be mindful of the total daily acetaminophen dose if the combination tramadol and acetaminophen dosage formulation is utilized. Tramadol dosage should be titrated slowly to minimize adverse effects, and there should be adherence to dosing guidelines for older adults.

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