Treatment of Pain

Analgesic Therapies

Non-steroidal anti-inflammatory drugs (NSAIDs) and steroids (see Corticosteroid Therapy) can be useful for acute pain relief in patients with rheumatoid arthritis (RA). In osteoarthritis, studies have shown that acetaminophen may have efficacy, although more people find NSAIDs to be effective. Thus, the use of nonnarcotic analgesics may be effective in those patients with a predominance of mechanical pain only. Acetaminophen can be an effective adjunct in many RA patients, provided that doses of 2,000-4,000 mg/day are used (in the correct clinical context). Higher doses or use in patients with comorbidities may be associated with hepatic or other toxicity.

Other analgesics commonly used to treat mechanical pain include tramadol, or tricyclic and other antidepressants. Tramadol may be used for brief periods of activity-related pain or in preparation for corrective surgery or joint replacement. Tramadol is a centrally acting analgesic with opioid and nonnarcotic effects and may be used at doses of 50-100 mg two or three times daily as needed for pain. The use of antidepressants at bedtime may promote better sleep and provide modest nighttime and daytime analgesia. Commonly used agents include amitriptyline (10-75 mg) or trazodone (25-100 mg) at bedtime. Other antidepressant medications, including duloxetine, are used for pain control in osteoarthritis and diffuse pain syndromes. Some patients who do not achieve the desired level of pain control with classical analgesics may turn to non-prescribed alternatives, including cannabis. One meta-analysis found a cannabis use rate of 26.0% among patients with inflammatory rheumatic disease, including RA. However, there is no good quality evidence that cannabinoid use for non-cancer pain relief is safe and effective.

Stronger analgesics (i.e., codeine, hydrocodone, oxycodone) should not be used routinely in RA. Patients should be cautioned about their prolonged use as these agents are addictive and can be associated with tachyphylaxis with chronic use. Chronic opioid use is a growing problem; among patients with RA, chronic opioid use more than doubled from 7.4% in 2002 to 16.9% in 2015.

Topical Analgesia

Analgesia may also be achieved through the use of topical heat or cold applications. Clinicians and therapists usually advise cold applications in the setting of active inflammatory synovitis or joint effusions. This is usually accomplished using ice packs, applied for 15 to 30 minutes, repeated every 2 to 6 hours as needed and should be accompanied by rest. Cold packs may tend to increase joint stiffness but are usually effective at reducing inflammation and providing local analgesia.

In contrast, the application of heat is often effective at relieving joint stiffness and muscle spasm or in the treatment of contracture or limited range of motion (i.e., adhesive capsulitis). Local heat may be applied in the form of hot packs, infrared therapy, hydrotherapy, or hot paraffin wax baths.

Topical creams (e.g., containing methyl salicylate) for joint pain tend to warm the skin but have little effect on joint or periarticular pain. Topical methyl salicylate creams are weakly analgesic and may be associated with systemic absorption that can lead to detectable serum salicylate levels and toxicity (e.g., salicylate intoxication, gastric toxicity, drug interactions). Capsaicin is a topical analgesic agent that depletes the sensory nerve fibers of substance P (a local mediator of pain) and is indicated for the treatment of mechanical pain. Its full analgesic effect requires that it be applied over the painful joint three to four times daily. It may be associated with a tingling or burning sensation. Other topical agents include topical Cannabidiol (CBD), topical forms of other NSAIDs, topical analgesics (e.g., lidocaine) and compounds containing menthol or camphor. The precise mechanism of action of these medications is not known.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are often the initial choice of therapy in RA patients, especially in those with early or slowly progressive disease. These agents are particularly effective at relieving joint pain, stiffness and mild to moderate swelling. Commonly, these agents are first initiated while diagnostic testing or imaging and serial observation are used to establish the diagnosis of an early arthritis patient. These compounds are unified by their analgesic, anti-inflammatory, antipyretic and antiplatelet properties that are primarily mediated by the inhibition of COX and PGs. Although these agents are effective in treating the pain and inflammatory symptoms associated with RA, they have not been shown to alter the natural history of the disease.

NSAIDs should be considered as adjunctive or palliative analgesic or anti-inflammatory therapy in early RA and throughout its course. Table 9-1 lists the commercially available NSAIDs, doses, schedule of use and range of dosing. Although all NSAIDs are on average equally effective, patient responses to and preferences for a specific NSAID may differ. The choice of NSAID therapy should not be based on class of drug but rather based on the cost, availability, dosing, duration of effect, anticipated toxicities, patient preference and physician experience with the agent. Moreover, the use of NSAIDs should be avoided in some patients, especially those with a documented aspirin or NSAID allergy, a history of peptic ulceration or GI bleeding and those with uncontrolled hypertension or CV risks.

While analgesic effects can be achieved with low or moderate doses of NSAIDs, the anti-inflammatory effects (and toxicity potential) will increase with higher doses. The onset of effect may be within days (analgesic effect) or weeks (anti-inflammatory effect). Therefore, a reasonable trial of a particular NSAID (usually between 2 to 6 weeks) should be given before prescribing another NSAID.

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NSAIDs in Early RA

Although from 1981 through 1996, disease-modifying antirheumatic drug (DMARD) use increased from 32% to 47%; NSAID use declined (86% to 76%) in the same era. Nonetheless, initial therapy with NSAIDs is commonplace and appropriate while the early arthritis patient is being evaluated. There are very few studies that analyze the benefits or risks of NSAIDs in early RA.

Neustadt reported on the use of NSAID monotherapy in 1446 early arthritis patients and showed that only 50% stayed on NSAIDs for a year. Only 2% of those remaining on therapy were able to achieve remission and there was no difference in radiographic progression between patients taking ibuprofen or etodolac. Choy and colleagues compared the effect of diclofenac or sulfasalazine (SSZ) therapy in early RA patients and although comparable clinical improvement (Ritchie index, swollen joints, pain scores) was shown, radiographic outcomes at 12 months were different. SSZ-treated patients had less radiographic progression and fewer new erosions (mean of 2.3 vs 10.5) compared with those taking diclofenac after 12 months of therapy.

COX-1 and COX-2 Inhibitors

The analgesic, anti-inflammatory, antipyretic and antiplatelet properties of NSAIDs are primarily mediated by the inhibition of cyclooxygenase (COX) enzymes and, consequently, decreased production of prostaglandins. The two major COX isoforms, COX-1 and COX-2, differ in their tissue distribution and biologic function. COX-1 is involved in homeostatic “housekeeping” functions and is found in the stomach, where it promotes the production of PGE₂ and PGI₂ (prostacyclin), leading to local vasodilatory effects important in maintaining mucosal integrity. In the kidney, COX-1 is also responsible for vasoregulatory prostanoids that help to regulate the glomerular filtration rate. In platelets, COX-1 is important in the production of thromboxane A₂ and regulates platelet aggregation.

COX-2 expression may be constitutive or induced by inflammation, and thus it is expressed in the synovium on atheromatous plaques and on neoplastic cells. COX-2 plays an important role in ovulation (and implantation) and in fever/inflammation as well. The constitutive expression of COX-2 by the kidney in part explains the low incidence of edema and renal adverse effects sometimes seen with selective COX-2 inhibitors. COX-2 inhibitors were initially developed to provide control of inflammation and pain without the inherent GI toxicities seen with nonselective COX inhibitors.

Thus it appears that the newer COX-2–selective inhibitors are equipotent anti-inflammatory, analgesic and antipyretic agents, with little or no platelet effects. While the COX-2 inhibitors have been shown to decrease rates of GI erosions, colonic perforations, ulcerations and bleeds, the magnitude and consistency of this finding has not been sufficient for the Food and Drug Administration (FDA) to allow this claim in their product labeling. Ongoing research suggests that COX-2 inhibition may be helpful in preventing colorectal cancer or adenomatous polyposis. Nonacetylated salicylates (e.g., salsalate) are weak inhibitors of COX and their mechanism of action is poorly understood.

Aspirin

Aspirin is cheap but is seldom used to manage pain or inflammation in RA. Aspirin use has been replaced by NSAIDs, which are safer and easier to administer. Doses of 3-4 g/day (serum salicylate levels of 90-100 mg/kg) are effective but may be associated with significant toxicity and the need for frequent (every 4 to 6 hours) dosing. Aspirin is a nonselective COX inhibitor. It binds to the COX-1 enzyme on platelets and irreversibly inactivates it. Thus, thromboxane production and platelet aggregation are inhibited for the life span of the platelets (approximately 1 week), long after aspirin has disappeared from the circulation. In contrast, the antiplatelet effects of other nonselective COX inhibitors are reversible and are only seen when the drug is present. Thus, low doses of aspirin provide effective antiplatelet therapy and may be used to prevent myocardial infarction (MI) and stroke. NSAIDs, because of their short half-life and reversible antiplatelet action, are not thought to exert the same effect.

Studies found that if a nonselective NSAID (ibuprofen) was taken before aspirin, the antiplatelet effect of aspirin was blunted. This was thought to occur because ibuprofen blocked the access of aspirin to its COX-1 binding site. A retrospective analysis of the Physicians Health Study suggested that persons who had taken regular NSAIDs did not experience the same cardioprotective benefits as with aspirin. The optimal way to prescribe NSAIDs for patients who also require low-dose aspirin is not clear. One option is to use a COX-2–selective drug, but there is a suggestion that combining aspirin with a COX-2–selective drug may attenuate the GI safety of the COX-2 drug. Also, large trials of COX-2 inhibitors failed to show any cardioprotective effect when background low-dose aspirin was used. Additional clinical studies are needed to resolve these questions.

Nonacetylated Salicylates

Nonacetylated salicylates, such as salsalate (Disalcid), sodium salicylate, choline magnesium trisalicylate (Trilisate) and diflunisal (Dolobid), have minimal effects on platelet aggregation and do not alter bleeding time. Limited data also indicate that they are less likely to cause peptic ulceration. However, there is a lack of large controlled clinical trials comparing the efficacy and safety of nonacetylated salicylates with nonselective NSAIDs or COX-2–selective agents.

There are many nonselective COX inhibitors (Table 9.1) that vary in their respective abilities to inhibit COX-1 and COX-2. Apart from pharmacokinetic characteristics, other potential differences among them have not been extensively studied and they are generally assumed to have similar efficacy and toxicity profiles. However, some data suggest that some newer NSAIDs (e.g., meloxicam, etodolac and nabumetone) may preferentially inhibit COX-2 more so than COX-1 and may have less gastrointestinal (GI) toxicity than older nonselective NSAIDs.

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Selective COX-2 Inhibitors

Although there were once three selective COX-2 inhibitors (coxibs) available (celecoxib, rofecoxib and valdecoxib), two of these (rofecoxib, valdecoxib) have been removed from the market owing to the postmarketing identification of a marginally increased risk of cardiovascular (CV) events. Currently, only celecoxib remains on the market in the United States, although others, including etoricoxib and lumiracoxib, are available in other worldwide markets. Low doses of meloxicam offer some COX-2 selectivity.

The COX-2 inhibitors were developed because these were thought to be less likely to cause serious GI complications than the nonselective NSAIDs. While short-term trials have shown less GI complications (e.g., ulcerations, GI bleeding, etc.), there is a loss of this benefit with long-term use or background low-dose aspirin therapy. The coxibs are equal in efficacy to traditional NSAIDs but have the advantage of possible increased GI safety, limited interaction with warfarin, no effect on platelet function or bleeding time (hence, the potential for use perioperatively). These agents have been approved for use in RA and are commonly used in patients with early RA, but like other NSAIDs, are not thought to alter the course of disease.

The withdrawal of rofecoxib and valdecoxib has led to questions about the CV safety of the traditional nonselective NSAIDs. Therefore, all NSAIDs and coxibs carry the same black box warning caution with their use in patients with CV risk factors. Studies have shown the risk for cardiac events to be comparable between celecoxib and the 2 most widely available traditional NSAIDs, ibuprofen and naproxen.

Celecoxib

This agent was approved for use in RA in 1998 and is available in 100- and 200-mg capsules. The usual dose in RA and other inflammatory disorders is 200 mg taken once or twice daily with meals. Peak plasma levels are achieved in 3 hours and the half-life is 11 hours. Celecoxib is primarily metabolized by cytochrome P-450 2C9 and is primarily eliminated by hepatic metabolism.

It does not affect platelet aggregation or the anticoagulant effect of warfarin. While it does not affect platelet aggregation, concomitant use with warfarin results in a 12% to 15% increase in prothrombin time (PT). Toxicities appear similar to those of the other NSAIDs. The incidence of hypertension and peripheral edema was ≤2% in controlled clinical trials. In the Celecoxib Long-Term Arthritis Safety Study (CLASS), celecoxib was compared with ibuprofen and diclofenac in 2,200 RA and 5,800 osteoarthritis patients. The primary outcome was the complicated ulcer rate (e.g., GI bleeding, perforation, or obstruction). Although this trial showed fewer GI complications in the celecoxib group, patients taking celecoxib and aspirin (≤325 mg/day) failed to show any GI benefit from the COX-2 inhibitor. In other words, the risk of GI complications in patients taking celecoxib and low-dose aspirin and those taking nonselective NSAIDs was similar. In the CLASS trial, CV events were not increased by celecoxib when compared with other NSAIDs (e.g., diclofenac, ibuprofen). Nonetheless, higher doses of celecoxib (400 or 800 mg/day) have been associated with more CV events. In the 3-year Adenomatous Polyp Prevention (APP) trial, higher doses showed an increased risk of CV events with hazard ratios of 3.0 for 400 mg/day and 6.1 for 800 mg/day.

NSAID Toxicity

Toxicities associated with NSAIDs are largely a consequence of prostaglandin inhibition. GI toxicities are primarily due to the loss of cytoprotective (COX-1) prostaglandins and may manifest as dyspepsia, nausea, vomiting, gastric ulceration, colonic ulceration, or GI bleeding. GI toxicity is most likely in those receiving high-dose NSAIDs, multiple NSAIDs, the elderly, or those with a previous history of peptic ulcer disease and upper GI bleeding. These toxicities may be avoided in some patients by relying on proven prescribing guidelines (Table 9-2).

Symptoms of dyspepsia and nausea may be effectively treated with H₂ blockers (ie, ranitidine, cimetidine), but these agents do not protect against the development of gastric ulceration or bleeding. There is poor correlation between symptoms and endoscopic ulceration or bleeding, thus one cannot rely upon symptoms to assess the risk of gastric ulceration. Patients at risk for NSAID-related GI ulceration may benefit from misoprostol (a prostaglandin analogue) or proton pump inhibitors (PPIs) (e.g., omeprazole, lansoprazole, etc.) as these have been shown to prevent NSAID-induced GI ulceration and bleeding. However, patients placed on NSAID therapy should not routinely be treated with misoprostol or omeprazole prophylaxis.

Most treatment guidelines suggest that patients who are at risk for NSAID-induced peptic ulceration but must receive NSAID therapy should receive either a COX-2–selective drug or a nonselective NSAID with either misoprostol or PPI prophylaxis. Misoprostol frequently causes diarrhea and has to be administered two to four times daily. Therefore, many clinicians prefer to use a PPI in this clinical scenario. Preliminary studies indicate that the strategies of using either a COX-2–selective NSAID or a nonselective NSAID with a PPI result in similar GI protection. However, protection is not complete and, despite these preventive strategies, patients who have previously suffered GI bleeding have a high rate of recurrence of NSAID-associated GI complications.

Hence in high-risk individuals, it is prudent to avoid NSAIDs, if possible. Since NSAIDs are commonly used, the clinician should be aware of measures to limit NSAID toxicity (Table 9-2).

Renal toxicity due to NSAID therapy may manifest as edema, weight gain, uncontrolled hypertension, hyperkalemia, renal insufficiency, nephrotic syndrome (due to interstitial nephritis), or renal papillary necrosis. Vasodilating prostaglandins (PGI₂, PGE₂) are produced locally within the kidney and play an important part in the regulation of renal blood flow and the glomerular filtration rate. Their inhibition by NSAIDs may be deleterious in those with preexisting renal disease, congestive heart failure, ascites, or dehydration. All NSAIDs, including the COX-2 inhibitors, are capable of producing renal toxicity and should be used with caution in patients with any of the aforementioned conditions as well as in those patients with poorly controlled hypertension. If possible, NSAIDs should be avoided in patients with chronic renal insufficiency.

If NSAID therapy is initiated in a patient with a risk factor for renal toxicity, the blood pressure and serum creatinine concentration should be monitored periodically. NSAID therapy should be discontinued if these parameters are repeatedly abnormal without any other cause. NSAIDs may blunt the antihypertensive effects of diuretics and angiotensin-converting enzyme inhibitors.

As discussed earlier, patients taking COX-2 inhibitors and some nonselective NSAIDs may experience slightly higher rates of CV or thromboembolic events, presumably from the influence of these agents on hypertension or their ability to inhibit prostacyclin without affecting thromboxane A₂. This risk may be increased with higher doses, prolonged therapy and when used in patients at high risk for CV or thromboembolic events. Non-NSAID therapies should be considered in such patients.

Nonselective NSAIDs inhibit COX-1 on platelets and decrease thromboxane A₂ release and inhibit platelet aggregation. Thus aspirin and other nonselective NSAIDs prolong bleeding time and may have a significant anticoagulant effect. Symptoms of easy bruising and, less commonly, epistaxis can occur. These effects are significantly worsened by the concomitant use of anticoagulants (i.e., warfarin). Thus aspirin and nonselective NSAID therapy is generally avoided in patients receiving anticoagulants. Because COX-2 inhibitors do not affect platelet function, they may be used if a patient requires an NSAID and is also receiving warfarin or is about to undergo surgery and requires continuous pain control.

Less-common NSAID side effects include constipation, headache, somnolence, confusion (especially with indomethacin), paresthesias, tinnitus, rash or urticaria, hepatitis, syncope and anemia (from GI blood loss). Allergy to NSAIDs is uncommon but can be serious, resulting in urticaria, wheezing and angioedema. Such hypersensitivity is more common in patients who have asthma or nasal polyps. A person who is allergic to one NSAID is likely to have a similar reaction when exposed to aspirin or other NSAIDs. COX-2–selective drugs appear less likely to cause allergy. Rarely, NSAIDs have been implicated in causing aplastic anemia, aseptic meningoencephalitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, seizures, or mouth ulcers.

Several alternatives to NSAID therapy exist for the elderly, those who are intolerant of NSAIDs and those at high risk for renal, GI, hemorrhagic, or CV complications. In such individuals, pain may be treated with analgesic therapies, low-dose corticosteroids (if inflammatory symptoms exist), intraarticular corticosteroid injections (with localized joint disease), or physical therapy. Nonacetylated salicylates may provide greater protection from the renal and GI hazards of NSAID therapy since these agents are weak inhibitors of COX.

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NSAID Combined With an H₂-Receptor Antagonist or Proton Pump Inhibitor

Several fixed-dose combination formulations containing an NSAID either with an H₂-receptor antagonist or a proton pump inhibitor have been approved by the FDA for the relief of signs and symptoms of RA and osteoarthritis and to decrease the risk of developing upper GI ulcers. One combination formulation contains ibuprofen and famotidine (Duexis) and another contains enteric-coated naproxen and esomeprazole (Vimovo). The ability to reduce the risk of upper GI and/or gastric ulcer was assessed for both formulations in 6-month randomized, controlled clinical trials that compared the combination formulation with the NSAID alone. In these trials, each of the combination formulations significantly reduced the risk of upper GI ulcers over 6 months. In terms of overall safety, the types of AEs were consistent with those of the component agents.