Nonsteroidal Anti-inflammatory Drugs

OTC NSAIDs are indicated for self-treatment of pain rather than inflammation, and the dosing guidelines on the package should not be exceeded unless the patient is instructed to do so by a physician. Patients taking OTC products should be closely monitored for effectiveness of therapy and the development of toxicities. NSAIDs are the initial drug treatment of choice for rheumatoid arthritis since they work to reduce joint pain and swelling, and improve function. While their analgesic and anti-inflammatory properties provide benefit, NSAIDs do not alter the course of rheumatoid arthritis or prevent joint destruction. Their mechanism of action is related to the inhibition of prostaglandin (PG) synthesis. Cyclooxygenase (COX) serves as the rate-limiting enzyme in PG production. Inhibition of this enzyme decreases PG-induced initiation and maintenance of inflammatory responses. There is no significant clinical difference in efficacy among the NSAIDs, although patient response to individual agents varies greatly. The choice of NSAIDs should be based on cost, duration of action, and patient tolerability and acceptance. While the analgesic effect of NSAIDs is quick in onset, the anti-inflammatory effect may not be complete for 4–6 weeks. If a patient fails therapy with a particular NSAID at the recommended dosage, another NSAID from another chemical class should be tried. The side effects of NSAIDs should be considered in patients who are elderly, have comorbid disease states (hypertension, diabetes, congestive heart failure, renal failure, peptic ulcer disease), or may be taking concurrent medications (e.g., diuretics) that may reduce renal blood flow. The primary adverse effect of NSAIDs is a tendency to cause bleeding and ulcerations in the stomach. A strategy to manage this condition is to prescribe misoprostol (Cytotec) concurrently for patients to take with their NSAIDs. Since misoprostol is a synthetic prostaglandin, it both prevents and heals NSAID-induced ulcers. A fixed combination product of diclofenac and misoprostol is available commercially. This product has been designed for patients who are at increased risk of developing gastric or duodenal ulcers from NSAID therapy. Patients receiving this fixed combination therapy had a reported gastric ulcer rate of 3%–4%, compared to 11% with diclofenac alone. Combination products of misoprostol and other NSAIDs are also being developed.

Corticosteroids: Corticosteroids have been proven to rapidly and effectively reduce inflammation and relieve symptoms in patients with rheumatoid arthritis. However, the development of adverse effects with corticosteroids, when taken for extended periods of time and at higher doses, limits their use. Intra-articular injections of steroids are generally safe and effective when administered appropriately, and can provide patients with immediate relief. Injections directly into the joint may also allow the patient to regain more range of motion in joints that have become stiff and inflamed. Low-dose oral corticosteroids (10 mg of prednisone daily or the equivalent) are beneficial for patients during the following situations: acute flares, special life events, the period of therapy after a DMARD has been initiated but not yet reached full effect, or when unacceptable discomfort or functional limitations persist despite full-dose NSAID and/or DMARD therapy.

The patient should be closely monitored for the development of side effects such as adrenal suppression, Cushing’s syndrome, osteoporosis, glaucoma, cataracts, gastritis, and hypertension. In patients receiving steroids for only 1–2 weeks, the corticosteroid need not be tapered since adrenal suppression is minimal over such a short period of time. However, in patients receiving doses of corticosteroids for greater than one month, tapering should occur gradually and be proportional to the length of time that the patient was on corticosteroids. Slow tapering of glucocorticoids allows the body to resume its natural production of cortisol, which becomes suppressed when patients take exogenous sources of steroid. It may be necessary to decrease the dose of corticosteroid by 1 mg every 1–2 weeks if the patient experiences symptoms of rheumatoid arthritis or has other complaints. A goal of any corticosteroid therapy should be to limit the use of the corticosteroid and avoid long-term therapy if possible.

Disease-Modifying Antirheumatic Drugs: Since active disease leads to irreversible joint and bone damage, it is important to start patients on DMARD therapy as soon as possible. Initiation of DMARD therapy is crucial in the management of rheumatoid arthritis. For a patient with a confirmed diagnosis, therapy should not be delayed beyond three months if, despite full-dose NSAID therapy, he or she has continued joint pain, significant morning stiffness or fatigue, active synovitis, or persistent elevation in ESR. The goal is to intervene before joints become damaged. While NSAIDs and corticosteroids alleviate symptoms, joint damage can still occur during their use, and the disease will progress. Disease-modifying agents such as hydroxychloroquine (HCQ), sulfasalazine (SSZ), methotrexate (MTX), gold salts, d-penicillamine (DP), and azathioprine (AZA) are intended to reduce or prevent joint damage, preserve joint integrity and function, maintain patient productivity and reduce total healthcare costs of patients with rheumatoid arthritis.

DMARDs as a class have a relatively slow onset of effect (1–6 months) and each patient will respond differently to various agents. Each DMARD also has its own unique toxicities which require close monitoring in order to avoid adverse events (Table 2). Patients must be educated about the potential risks versus benefits before initiating therapy.

The best initial DMARD for treatment of rheumatoid arthritis has not been established. SSZ or HCQ is usually selected for patients with mild disease. Both are available generically and have convenient dosing schedules and favorable safety profiles. HCQ therapy requires no additional laboratory monitoring, although patients should receive eye exams every 6–12 months to detect the development of reversible retinal toxicity (i.e., decreased night vision, loss of peripheral vision). SSZ requires that patients have routine CBCs to detect possible development of blood dyscrasias. The onset of action of these therapies should be apparent within 1–6 months; if no response is seen after this time, a change in therapy is warranted.

Methotrexate is the drug of choice in patients who have a more severe form of the disease (for example, erosions or extra-articular manifestations). Low-dose, once-weekly therapy has become a mainstay of treatment because MTX is relatively inexpensive; the cost of monitoring for toxicity is less than that of monitoring with use of gold, penicillamine or immunosuppressive agents; and there is a high rate of clinical response. The onset of action is generally within several weeks of initiating therapy, and patients are likely to still be on treatment after 5 years. Other DMARDs do not have such a quick onset of effect or long-term patient tolerability.

Methotrexate therapy is usually initiated at 7.5 mg/week. This dosage may be either increased or decreased depending on efficacy or development of toxicity. The usual dose is from 7.5–15 mg/week. To aid patients in appropriately taking MTX therapy, specially designed dose packs are available. Each dose pack contains one month’s worth of MTX therapy. The tablets are grouped by weekly doses and clearly marked to improve patient adherence. All of the dose packs contain 2.5 mg MTX tablets but are available in different weekly doses.
Prior to beginning MTX therapy, it is necessary to perform baseline laboratory work. A CBC with differential, platelet count, liver function tests, hepatitis B and C studies, serum creatinine and chest x-ray should be obtained. Subsequently, every 1–2 months CBC with platelet count, AST, and albumin should be evaluated. These tests, along with routine chest x-rays, help to monitor for thrombocytopenia, leukopenia, anemia, renal insufficiency, liver fibrosis, and pulmonary changes that are associated with MTX therapy. Side effects such as nausea, vomiting, diarrhea, and stomatitis may develop. These side effects may be minimized with the administration of folic acid 1 mg/day. Concurrent administration of folic acid decreases the incidence of side effects by 50% without decreasing the clinical efficacy of MTX.20 It is also possible to split the MTX dose over 24 hours instead of taking all of the tablets at once, or administer MTX subcutaneously or intramuscularly should GI discomfort continue.

Contraindications and drug interactions are also considerations when initiating MTX therapy. Since it is highly teratogenic, MTX should not be given to pregnant or lactating females. Patients who are known alcoholics or have alcohol-associated liver disease should not receive MTX since hepatic fibrosis may develop. Methotrexate should also not be used in patients who are immunocompromised, are known to be nonadherent with therapy, or have existing blood dyscrasias. Patients should be educated to avoid excessive alcohol intake since it may contribute to the development of liver toxicity. Other drugs to be avoided include phenytoin (alters protein binding), trimethoprim/sulfamethoxazole (has anti-folate activity), aminoglycosides (is nephrotoxic) and probenecid (is nephrotoxic). Concurrent administration of any of these medications significantly increases the risk of developing toxicity.
Gold and penicillamine have been used for many years in the treatment of rheumatoid arthritis. Although neither agent is used frequently anymore, they may be utilized in refractory cases of rheumatoid arthritis. While patients respond successfully to gold therapy, many have to discontinue therapy within 1 year due to development of toxicity (anemia, leukopenia, thrombocytopenia, proteinuria) or decrease in efficacy. Penicillamine is comparable to gold in efficacy; however, side effects (nausea, vomiting, diarrhea, hypogeusia) limit its clinical use. A word of caution when using penicillamine is that 10% of patients who have an allergic reaction to penicillin will have a hypersensitivity to penicillamine; however, this is not an absolute contraindication to therapy

Immunosuppressive Agents: In addition to MTX, cyclophosphamide, cyclosporin A and AZA are immunosuppressive agents used to manage rheumatoid arthritis. These therapies are generally reserved for severe cases unresponsive to other treatments. These agents are effective in controlling the symptoms of rheumatoid arthritis but have the same toxicities associated with any chemotherapeutic agent. Side effects such as myelosuppression, hepatotoxicity, GI disturbances, and hemorrhagic cystitis are commonly seen with cyclophosphamide, cyclosporin A and AZA. Cyclosporin A has proven beneficial in patients who fail to respond to DMARD therapy but is more toxic than DMARDs. Women should be informed of the fetal risk associated with the agent being used, and appropriate measures should be taken to ensure effective contraception.

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