Managing Breakthrough Pain in Rheumatoid Arthritis

Managing Breakthrough Pain in Rheumatoid Arthritis

Scott Chappell
Scott Chappell

Galt Pharmaceuticals Director of Medical Affairs

Adjusting current DMARD (Disease Modifying Antirheumatic Drugs) therapy, utilizing non-pharmacologic therapies and employing NSAIDs play significant roles in managing breakthrough symptoms for rheumatoid arthritis (RA) management.

Managing Breakthrough Pain with Current DMARD Therapy

Managing of breakthrough symptoms with current DMARD therapy, the treatment options are guided by the 2021 American College of Rheumatology (ACR) guidelines.[1]

  1. Optimization of Current DMARD Therapy: If a patient is experiencing breakthrough symptoms, the first step is to optimize the current disease-modifying antirheumatic drug (DMARD) regimen. This may involve increasing the dose of the current DMARD or adding another conventional synthetic DMARD (csDMARD) such as methotrexate, hydroxychloroquine, sulfasalazine, or leflunomide.[1]

  2. Switching or Adding Biologic DMARDs (bDMARDs): If optimization of csDMARDs is insufficient, the next step is to consider biologic DMARDs. Options include TNF inhibitors (e.g., etanercept, adalimumab, infliximab), IL-6 receptor inhibitors (e.g., tocilizumab, sarilumab), T cell costimulatory inhibitors (e.g., abatacept), and B cell depleting agents (e.g., rituximab). [1-2]

  3. Targeted Synthetic DMARDs (tsDMARDs): For patients who do not respond adequately to bDMARDs, targeted synthetic DMARDs such as Janus kinase (JAK) inhibitors (e.g., tofacitinib, baricitinib, Upadacitinib) can be considered.[1]

  4. Switching Mechanisms of Action: If a patient fails to respond to one class of bDMARDs, switching to a different mechanism of action (e.g., from a TNF inhibitor to an IL-6 receptor inhibitor or a JAK inhibitor) is recommended. [3-4]

  5. Combination Therapy: Combining csDMARDs with bDMARDs or tsDMARDs can be effective in managing breakthrough symptoms and achieving better disease control. [1-2]

  6. Glucocorticoids: Short-term use of glucocorticoids can be considered for rapid symptom relief, but long-term use is generally discouraged due to potential adverse effects.[1][5]

These strategies should be tailored to the individual patient, considering factors such as disease severity, comorbidities, and previous treatment responses. Regular monitoring and a treat-to-target approach are essential to optimize outcomes.[1][6]

Non-Pharmacologic Interventions for Breakthrough Pain

The 2022 American College of Rheumatology (ACR) guidelines recommend several non-pharmacologic interventions for RA management. [7] 

  1. Exercise Therapy: Regular aerobic and strength exercises improve physical function and reduce pain.

  2. Therapeutic Patient Education: Educating patients on self-management strategies, including joint protection and energy conservation, is beneficial.

  3. Physical and Occupational Therapy: Tailored exercise programs, assistive devices, and ergonomic advice help maintain joint function and reduce pain.

  4. Orthoses and Assistive Devices: Devices like wrist splints and foot orthoses provide joint support and pain relief.

  5. Dietary Interventions: Diets such as the Mediterranean diet, which emphasizes vegetables, fruits, whole grains, and healthy fats, may have anti-inflammatory effects.

  6. Cognitive Behavioral Therapy (CBT): CBT helps manage the psychological impact of RA, improving overall quality of life.

  7. Balneotherapy: Mineral baths can provide symptomatic relief.

  8. Mind-Body Approaches: Techniques like mindfulness, meditation, and biofeedback can help manage pain and stress.

NSAIDs for Breakthrough Pain

NSAIDs are effective for managing breakthrough pain in RA by reducing inflammation and pain. However, NSAIDs should be used at the lowest effective dose for the shortest duration to minimize risks such as gastrointestinal complications and cardiovascular events.[3]

In summary, adjusting DMARD therapy, utilizing non-pharmacologic therapies, and employing NSAIDs for the proper patient can effectively manage breakthrough symptoms in RA, enhancing patient outcomes and quality of life.

References:

  1. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Fraenkel L, Bathon JM, England BR, et al. Arthritis Care & Research. 2021;73(7):924-939. doi:10.1002/acr.24596.
  2. Optimizing Outcomes in Rheumatoid Arthritis Patients With Inadequate Responses to Disease-Modifying Anti-Rheumatic Drugs. Pavelka K, Kavanaugh AF, Rubbert-Roth A, Ferraccioli G. Rheumatology (Oxford, England). 2012;51 Suppl 5:v12-21. doi:10.1093/rheumatology/kes111.
  3. The Management of First-Line Biologic Therapy Failures in Rheumatoid Arthritis: Current Practice and Future Perspectives. Favalli EG, Raimondo MG, Becciolini A, et al. Autoimmunity Reviews. 2017;16(12):1185-1195. doi:10.1016/j.autrev.2017.10.002.
  4. Optimizing Outcomes in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-TNF Treatment. Emery P. Rheumatology (Oxford, England). 2012;51 Suppl 5:v22-30. doi:10.1093/rheumatology/kes115.
  5. Strategies Toward Rheumatoid Arthritis Therapy; The Old and the New. Abbasi M, Mousavi MJ, Jamalzehi S, et al. Journal of Cellular Physiology. 2019;234(7):10018-10031. doi:10.1002/jcp.27860.
  6. Treating to Target in Established Rheumatoid Arthritis: Challenges and Opportunities in an Era of Novel Targeted Therapies and Biosimilars. Woodworth TG, den Broeder AA. Best Practice & Research. Clinical Rheumatology. 2015 Aug-Dec;29(4-5):543-9. doi:10.1016/j.berh.2015.10.001.
  7. 2022 American College of Rheumatology Guideline for Exercise, Rehabilitation, Diet, and Additional Integrative Interventions for Rheumatoid Arthritis. England BR, Smith BJ, Baker NA, et al. Arthritis & Rheumatology (Hoboken, N.J.). 2023;75(8):1299 1311doi:10.1002/art.42507.

 

 

 

 

Brief History and Proper Utilization of NSAIDs

Brief History and Proper Utilization of Nonsteroidal Anti-inflammatory Drugs

Scott Chappell
Scott Chappell

Galt Pharmaceuticals Director of Medical Affairs

Background on NSAIDs

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a long and storied history, beginning with the use of salicylate-containing willow bark for pain and fever relief in ancient cultures. The active component, salicylic acid, was chemically synthesized in 1860, leading to the development of acetylsalicylic acid (aspirin) in 1897. Aspirin’s success spurred the development of other NSAIDs, which were initially organic acids but later included non-acidic compounds.

NSAIDs exert their effects primarily through the inhibition of cyclooxygenase (COX) enzymes, which are crucial for prostaglandin synthesis. There are two main isoforms: COX-1, which is involved in maintaining physiological functions such as gastrointestinal protection and platelet aggregation, and COX-2, which is induced during inflammation and mediates pain and fever. The discovery of these isoforms in the 1990s led to the development of selective COX-2 inhibitors (coxibs), designed to reduce gastrointestinal side effects associated with non-selective NSAIDs. However, the introduction of coxibs like celecoxib and rofecoxib revealed significant cardiovascular risks, leading to the withdrawal of rofecoxib from the market in 2004. This highlighted the need for a balance between efficacy and safety in NSAID therapy.

NSAIDs have widespread use and therapeutic benefits, but note that they are associated with adverse effects, including gastrointestinal ulcers, cardiovascular events, and renal toxicity. Strategies to mitigate these risks include using the lowest effective dose for the shortest duration and co-prescribing gastroprotective agents like proton-pump inhibitors for high-risk patients. The ongoing evolution of NSAIDs aims to enhance their safety while maintaining their efficacy in treating pain, inflammation, and fever.

Mitigating the Risks for Patients Who Need to use NSAIDs

To monitor and mitigate the risks for patients who need to use NSAIDs, especially those with a history of gastrointestinal (GI) bleeding, cardiovascular disease, or renal impairment, several strategies can be employed:

  1. Use the Lowest Effective Dose for the Shortest Duration: This is a fundamental principle to minimize adverse effects. The FDA emphasizes this approach to reduce the risk of GI bleeding, cardiovascular events, and renal toxicity.
  2. Gastrointestinal Protection: For patients with a history of GI bleeding or at high risk, co-therapy with proton-pump inhibitors (PPIs) or misoprostol is recommended. The American College of Gastroenterology advises using a COX-2 inhibitor plus a PPI or misoprostol for high-risk patients. Testing and eradicating  pyloriinfection can also reduce the risk of peptic ulcers in NSAID users.
  3. Cardiovascular Risk Management: The American Heart Association recommends avoiding NSAIDs, particularly COX-2 inhibitors, in patients with cardiovascular disease. If NSAIDs are necessary, naproxen may be preferred due to its relatively lower cardiovascular risk. Monitoring blood pressure and managing other cardiovascular risk factors are crucial.
  4. Renal Function Monitoring: Regular monitoring of renal function, fluid retention, and electrolyte levels is essential, especially in patients with preexisting renal impairment, heart failure, or those on diuretics or ACE inhibitors. The FDA and other literature recommend avoiding NSAIDs in patients with advanced renal disease and using alternative therapies when possible.
  5. Patient Education and Monitoring: Educate patients about the signs and symptoms of GI bleeding, cardiovascular events, and renal impairment. Regular follow-up and prompt evaluation of any adverse symptoms are critical.

By implementing these strategies, clinicians can better manage the risks associated with NSAIDs used in vulnerable patient populations.

Patient Groups That Should Avoid NSAIDs

Certain patient groups should avoid using nonsteroidal anti-inflammatory drugs (NSAIDs) due to their potential adverse effects, including gastrointestinal (GI) ulcers, cardiovascular events, and renal toxicity.

  • Elderly patients are at increased risk for NSAID-related adverse effects, including GI bleeding, renal impairment, and cardiovascular events. Elderly patients, especially those with comorbidities, are particularly vulnerable to these risks.
  • Patients with a history of peptic ulcer disease or gastrointestinal bleeding should avoid NSAIDs due to a significantly increased risk of GI bleeding. The FDA notes that these patients have a greater than 10-fold increased risk for developing a GI bleed when using NSAIDs.
  • Patients with cardiovascular disease or patients at high risk for cardiovascular events should avoid NSAIDs, particularly COX-2 inhibitors, due to the increased risk of myocardial infarction and stroke. The American Heart Association advises against the use of NSAIDs in patients with established cardiovascular disease.
  • Patients with renal impairment, heart failure, or chronic kidney disease (CKD) should avoid NSAIDs due to the risk of worsening renal function and potential for acute kidney injury. The National Comprehensive Cancer Network (NCCN) guidelines recommend caution in these patients to prevent renal toxicities.
  • Patients on concurrent anticoagulant or corticosteroid therapy should avoid NSAIDs due to the increased risk of GI bleeding and other complications. The NCCN guidelines also emphasize the increased bleeding risk when NSAIDs are used with anticoagulants.

List of NSAIDs Available in the United States

The following is a list of commonly available NSAIDs in the United States by generic and brand name:

Ibuprofen (Advil®, Motrin®, IBU®)

Naproxen (Aleve®, Naprosyn®, Naprelan®)

Diclofenac (Voltaren®, Cataflam®)

Celecoxib (Celebrex®)

Meloxicam (Mobic®)

Indomethacin (Indocin®)

Ketorolac (Toradol®)

Etodolac (Lodine®)

Piroxicam (Feldene®)

Sulindac (Clinoril®)

Diflunisal (Dolobid®)

Salsalate (Disalcid®)

Oxaprozin (Daypro®)

Nabumetone (Relafen®)

Flurbiprofen (Ansaid®)

Fenoprofen (Nalfon®)

Meclofenamate (Meclomen®)

Tolmetin (Tolectin®DS)

NSAIDs are commonly used to treat a range of conditions, from minor aches and pains to chronic diseases such as arthritis. As a result, NSAIDs are highly effective for conditions like headaches, menstrual cramps, sprains, and inflammatory disorders such as osteoarthritis and rheumatoid arthritis.

NSAIDs are highly beneficial for managing pain and inflammation, but like all medications, they should be used with care, balancing their effectiveness against potential side effects.

References

  1. Vane JR, Botting RM. Mechanism of Action of Nonsteroidal Anti-Inflammatory Drugs. The American Journal of Medicine. 1998;104(3A):2S-8S; discussion 21S-22S.K. D.
  2. Rainsford, “ANTI-INFLAMMATORY DRUGS IN THE 21ST CENTURY,” Sub-Cellular Biochemistry. 2007;42:3-27
  3. Vonkeman HE, van de Laar MA. “Nonsteroidal Anti-Inflammatory Drugs: Adverse Effects and Their Prevention,” Seminars in Arthritis and /Rehumatism. 2010;39(4):294-312.
  4. Wehling M., Non-Steroidal Anti-Inflammatory Drug Use in Chronic Pain Conditions With Special Emphasis on the Elderly and Patients With Relevant Comorbidities: Management and Mitigation of Risks and Adverse Effects. European Journal of Clinical Pharmacology. 2014;70(10):1159-72.
  5. Antman EM, Bennett JS, Daugherty A, et al. Use of Nonsteroidal Antiinflammatory Drugs: An Update for Clinicians: A Scientific Statement From the American Heart Association. Circulation. 2007;115(12):1634-42.
  6. Bouck Z, Mecredy GC, Ivers NM, et al. Frequency and Associations of Prescription Nonsteroidal Anti-Inflammatory Drug Use Among Patients With a Musculoskeletal Disorder and Hypertension, Heart Failure, or Chronic Kidney Disease. JAMA Internal Medicine. 2018;178(11):1516-1525. doi:10.1001/jamainternmed.2018.4273.
  7. Lanza FL, Chan FK, Quigley EM. Guidelines for Prevention of NSAID-related Ulcer Complications. The American Journal of Gastroenterology. 2009;104(3):728-38.
  8. Wilcox CM, Allison J, Benzuly K, et al. Consensus Development Conference on the Use of Nonsteroidal Anti-Inflammatory Agents, Including Cyclooxygenase-2 Enzyme Inhibitors and Aspirin. Clinical Gastroenterology and Hepatology : The Official Clinical Practice Journal of the American Gastroenterological Association. 2006;4(9):1082-9.
  9. Domper Arnal MJ, Hijos-Mallada G, Lanas A. Gastrointestinal and Cardiovascular Adverse Events Associated With NSAIDs. Expert Opinion on Drug Safety. 2022;21(3):373-384.
  10. Ković SV, Vujović KS, Srebro D, Medić B, Ilic-Mostic T. Prevention of Renal Complications Induced by Non- Steroidal Anti-Inflammatory Drugs. Current Medicinal Chemistry. 2016;23(19):1953-64. 
  11. LaForge JM, Urso K, Day JM, et al. Non-Steroidal Anti-Inflammatory Drugs: Clinical Implications, Renal Impairment Risks, and AKI. Advances in Therapy. 2023;40(5):2082-2096.
  12. Ribeiro H, Rodrigues I, Napoleão L, et al. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Pain and Aging: Adjusting Prescription to Patient Features. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2022;150:112958.
  13. Domper Arnal MJ, Hijos-Mallada G, Lanas A. Gastrointestinal and Cardiovascular Adverse Events Associated With NSAIDs. Expert Opinion on Drug Safety. 2022;21(3):373-384.
  14. Nam YH, Brensinger CM, Bilker WB, et al. Nonsteroidal Anti-Inflammatory Drug Choice and Adverse Outcomes in Clopidogrel Users: A Retrospective Cohort Study. PloS One. 2018;13(3):e0193800. doi:10.1371/journal.pone.0193800.