Treatment of RA is complex, and disability reduction and pain management are variable. While RA treatment focuses on alleviating disease activity and improving physical function through early use of DMARDs, treatment of inflammation and pain to control symptoms is also important. RA pharmacotherapy should first consist of disease-modifying drugs, such as DMARDs with possible corticosteroids, to reduce and prevent joint damage and maintain function. Secondly for pharmacological treatment of inflammation and pain, there should be sufficient understanding of the risks and benefits of NSAIDs, corticosteroids, analgesics and adjuvant therapy to treat this complex patient population with RA.
1. disease-modifying antirheumatic drugs (DMARDs)
According to the ACR, DMARDs are the first-line therapeutic agents for RA. DMARDs reduce pain and inflammation, reduce and prevent joint damage, and protect joint function and structure. They are generally divided into non-biologic (conventional synthetic) and biologic (produced by recombinant DNA technology). The most common non-biologic DMARDs include: methotrexate, salbutamol and hydroxychloroquine, while the most common biologic DMARDs are etanercept and adalimumab.
Many studies have found that early intervention (within one year of symptom onset, preferably 3 months-4 months before onset) improves prognosis, as many joint space narrowing and erosions leading to RA-related disability occur in the first two years of diagnosis. It has also been noted that early treatment with DMARDs has better response rates and may reduce the course of joint damage.
If rheumatic disease-related healthcare professionals monitor patients with RA, the results show that they have a better prognosis. Therefore, it is recommended that when patients have suspected or show evidence of RA, tests including complete blood count, ESR, CRP, transaminases, blood urea nitrogen and creatinine levels are performed once started, and the ACR provides guidelines for DMARDs monitoring, depending on the patient taking DMARDs with more variable side effects, such as white blood cell decline and liver and kidney damage.
2. Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are the first line of therapeutic use to improve inflammation, pain and function. NSAIDs have only anti-inflammatory and analgesic properties and are effective in the treatment of chronic inflammatory pain. The most commonly used NSAIDs include: ibuprofen, naproxen, diclofenac, indomethacin, diflunisal, meloxicam, and celecoxib.
Studies have demonstrated that NSAIDs are superior to acetaminophen in pain treatment prognosis, function, and effectiveness. However, NSAIDs do not have disease-modifying effects and should not be used alone in the pharmacological treatment of RA, but may be used in combination with DMARDs.
Before NSAIDs treatment, physicians must consider their potential risks and side effects. Gastrointestinal side effects are common in the use of NSAIDs and range from dyspepsia to life-threatening gastrointestinal bleeding. Gastrointestinal risks increase with age, coexisting conditions and certain medications.
A history of gastrointestinal bleeding, nonselective NSAID use, high-dose NSAID use, alcohol consumption, smoking, antithrombotic agents, and corticosteroid therapy increase the risk of gastrointestinal side effects. Cardiovascular risks are also associated with NSAIDs treatment, including increased risk of edema, hypertension, heart failure, and myocardial infarction. In addition, renal side effects should be considered due to the risk of fluid retention, electrolyte disturbances, increased blood pressure, and potential nephrotoxicity.
Drug-drug interactions associated with the use of NSAIDs are often the cause of side effects. the combination of NSAIDs with anticoagulants and antiplatelet therapy increases the risk of bleeding through a cumulative effect; the combination of antihypertensives and diuretics with NSAIDs can lead to a reduced antihypertensive effect and an increased risk of nephrotoxicity. In addition, the combination of NSAIDs with systemic steroids increases the risk of many side effects, including gastrointestinal ulceration, bleeding, edema, and hypertension.
The possible risks of NSAIDs do not negate the critical role of this class of drugs in RA. Its importance in combination with condition-relieving drugs is to reduce pain and improve function.
The minimum dose, frequency and duration recommended to reduce the risk of side effects should also take into account the type of NSAID chosen. In general, with the exception of celecoxib, almost all non-selective NSAIDs, such as diflunisal, ibuprofen, naproxen, diclofenac, indomethacin and meloxicam, inhibit both cox-1 and cox-2 with greater gastrointestinal risk. Selective NSAIDs inhibit cox-2 only, with reduced gastrointestinal risk but increased cardiovascular risk. Celecoxib (selective NSAID) should be considered for patients with increased gastrointestinal risk, and selective NSAIDs should be avoided for patients at high risk for cardiovascular events.
To help reduce gastrointestinal side effects, proton pump inhibitors (PPIs) such as lansoprazole, pantoprazole or rabeprazole may be added, and treatment with NSAIDs should also be avoided in patients with renal dysfunction.
3.Topical NSAIDs
Topical NSAIDs are effective for local, restrictive, superficial pharmacotherapy of joint inflammation and reduce systemic absorption, side effects, and drug-drug interactions. Topical NSAIDs include diclofenac gels and patches. Although there is a lack of evidence to support the use of topical NSAIDs for RA, there is evidence to support their use in other chronic pain conditions, such as osteoarthritis pain control, with at least comparable effects to systemic NSAIDs but with fewer side effects. Because of reduced systemic absorption, topical NSAIDs may be considered for use in patients who are unable to take oral NSAIDs. Patients should be told not to use them on broken or inflamed skin, to avoid bandaging or heating, and that topical NSAIDs have a maximum dose per joint and an upper limit on the total daily dose.
4. Topical capsaicin
Deal and colleagues found that more than 80% of patients with knee osteoarthritis and RA felt that topical capsaicin could relieve pain, and the ACR conditionally recommends its use in patients with osteoarthritis, whose risk is low. Topical capsaicin may also be used as an adjunctive analgesic. When applied to joints, 3-4 times daily is recommended, in addition to which patients need to be cautioned not to use it on open, inflamed skin, heat, or wraps. If there is any skin irritation or discomfort, it must be discontinued.
5.Corticosteroids
Corticosteroids are an effective drug for controlling inflammation and pain in joints. Low doses of corticosteroids, such as prednisone (less than 10 mg per day), are effective in reducing joint inflammation and pain. Within a few days of starting corticosteroid use, patients’ symptoms can rapidly improve.
Early morning dosing appears to be more effective in relieving RA symptoms than later time dosing. However, in the absence of signs and symptoms of inflammation, corticosteroids are not recommended for routine RA pain management.
Similar to DMARDs, corticosteroids have some disease-relieving effects and have been shown to slow the process of joint destruction, reduce inflammation, and increase the rate of remission. Interruption of use often results in relapse and even requires concomitant use of DMARDs.
Systemic use of corticosteroids is associated with many side effects, including immunosuppression, hypertension, dyslipidemia, diabetes, osteoporosis, Cushing’s syndrome, gastrointestinal bleeding, weight gain, fluid retention, glaucoma, and cataracts. Before giving corticosteroids, the physician should first take a medical history and treat any of these conditions before administering the drug to reduce the risk of side effects. The patient’s current medication should also be evaluated. For example, concomitant treatment with NSAIDs and corticosteroids increases the risk of gastrointestinal events.
PPI initiation therapy has been shown to help prevent steroid-related peptic ulcers (PUD) and gastrointestinal bleeding, especially with concomitant NSAID or antiplatelet/anticoagulant use, a history of PUD, gastrointestinal bleeding, or advanced age. .
Adequate calcium intake, weight-bearing exercises, and avoidance of smoking and excessive alcohol consumption may reduce the risk of complications in patients. To reduce side effects, we should give the lowest dose with the shortest cycle and taper the corticosteroid dosage during periods of less active disease and remission. The starting dose of corticosteroids is highly variable.
For long-term treatment (more than 3 months), preventive steps must be taken to reduce the risk of long-term side effects. Patients should receive 1000 mg-1220 mg of calcium and 400 IU-800 IU of vitamin D daily. Bisphosphonates are important for the prevention of osteoporosis.
Intra-articular corticosteroid injections are indicated for RA treatment to help reduce synovitis in affected joints. Joint injections are effective, but are not indicated for joints that have developed involved joint spread, and the same joint should not be injected more than once in a 3-month period.
6.Acetaminophen
Acetaminophen inhibits prostaglandins, but it has a weak anti-inflammatory effect. Although the ACR considers NSAIDs to be more effective than acetaminophen, acetaminophen is still recommended as first-line therapy (especially in the elderly) because of its fewer side effects.
When considering initiating acetaminophen therapy in patients with RA, it is important to understand the lack of beneficial evidence supporting it and the risks of NSAID therapy. Second, acetaminophen may be used as first-line therapy for patients with pain management and a high risk of side effects with NSAIDs, taking into account coexisting conditions, age, or current medications.
Patients should be informed about coexisting conditions and evaluated for potential complicating factors, such as liver dysfunction. In addition, acetaminophen is safe when the dose is in the recommended range.
7. Opioids
Opioids work by blocking the body’s pain receptors, but have no anti-inflammatory effect and are the primary drug for RA medication. Opioids can be used for long-term treatment of pain, and their side effects need to be concerned. In a Cochrane review of opioids in the treatment of RA pain, whittle and colleagues found little evidence of benefit, but also noted an increased risk of adverse events. Opioids are an alternative treatment option when there is a contraindication or treatment failure, but patients should be evaluated for coexisting conditions and concomitant medications that may be associated with an increased risk of adverse events with opioid use. It is also recommended that patients be evaluated for potential abuse potential.
Weaker medications, such as tramadol, should be used as a starting drug and titrated appropriately. “Start slow, go slow” is used as the basis for initiation and opioid therapy to reduce the risk of side effects. Patient education should be provided regarding drug side effects, such as sedation and constipation. Driving or operating machinery while taking opioids is prohibited.
8.Other adjuvant therapy
Other adjuvant therapies may be considered to have analgesic effects, including antidepressants, anticonvulsants, muscle relaxants, and topical treatments, but these approaches have very limited evidence support for RA treatment.
Antidepressants are used as adjunctive therapy in many chronic pain disorders for pain relief and to treat underlying depression. Among antidepressants, the 5-hydroxytryptamine norepinephrine reuptake inhibitor venlafaxine and the tricyclic antidepressant amitriptyline have been shown to: have partial analgesic effects in addition to being used for depression treatment. However, evidence for selective 5-hydroxytryptamine reuptake inhibitors (SSRIs) is scarce.
Despite the specific role of antidepressants in the treatment of RA, a retrospective study found: no strong evidence to support the benefit of SSRIs in the treatment of pain in RA patients, while conflicting evidence was found for the use of TCAs. Adjunctive treatment with antidepressants in RA patients may be appropriate for those with depression. Antidepressants may not directly reduce pain, but treatment of other underlying conditions may improve function.
Anticonvulsants, such as gabapentin, are used in the treatment of many central neuropathic pains, such as fibromyalgia and neuropathy. Although thought to be used in chronic pain management, few clinical trials have demonstrated their effectiveness in RA analgesia.