What is the recommended pharmacologic and non‑pharmacologic management of pain in patients with connective‑tissue diseases such as systemic lupus erythematosus, systemic sclerosis, mixed connective‑tissue disease, or polymyositis?

Management of Pain in Connective Tissue Diseases

First-Line Approach: Non-Pharmacological Management

For chronic, non-inflammatory pain in connective tissue diseases, physical activity and aerobic exercise must be the initial therapeutic intervention before prescribing medications. 1

Exercise and Physical Therapy

• Aerobic exercise reduces pain severity and improves physical function in patients with systemic lupus erythematosus (SLE), with evidence showing improvement in aerobic capacity and reduction in fatigue 1
• Individual and group physical therapy should be implemented for systemic sclerosis patients, particularly targeting hand function and physical capacity 1
• Orofacial exercises improve microstomia in systemic sclerosis 1
• Exercise programs in Sjögren's syndrome significantly improve aerobic capacity, fatigue, perceived exertion, and depression 1

Patient Education and Self-Management

• Patient education and self-management support improve health-related quality of life, hand function, and ability to perform daily activities in systemic sclerosis 1
• Psychosocial interventions should be considered for SLE patients to improve quality of life, anxiety, and depressive symptoms 1

Pharmacological Management Algorithm

For Inflammatory Articular Pain (Frequent Episodes)

NSAIDs are recommended as first-line drug treatment for patients with pain and stiffness from inflammatory joint involvement. 1

• NSAIDs reduce frequency and severity of inflammatory symptoms 1
• In patients with increased gastrointestinal risk, use non-selective NSAIDs plus gastroprotective agents (proton pump inhibitors preferred, with relative risk 0.40 for serious GI events), or selective COX-2 inhibitors (relative risk 0.18 versus NSAIDs for serious GI events) 1
• Critical caveat: NSAIDs carry increased risk of renal side effects in lupus nephritis patients, including acute renal failure, sodium retention, and reduced glomerular filtration rate 2
• Monitor closely for hepatotoxicity, particularly with high-dose aspirin in SLE 2
• Hydroxychloroquine may be considered for patients with frequent articular pain episodes, particularly in Sjögren's syndrome with joint involvement 1

For Chronic, Non-Inflammatory Pain

Avoid repeated use of NSAIDs or glucocorticoids; instead, use antidepressants and anticonvulsants as first-line pharmacotherapy. 1

• Tricyclic antidepressants (amitriptyline), SSRIs, or SNRIs for chronic musculoskeletal pain 1, 3
• Gabapentin or pregabalin for chronic neuropathic pain 1, 3
• Warning: Amitriptyline may exacerbate dryness symptoms in Sjögren's syndrome 1

For Inadequate Response to First-Line Therapy

• Analgesics such as acetaminophen may be considered for pain control when NSAIDs are insufficient, contraindicated, or poorly tolerated 1, 3
• Opioids must not be used based on recent epidemiological data confirming harm 1

For Localized Musculoskeletal Inflammation

• Corticosteroid injections directed to the local site of musculoskeletal inflammation may be considered 1
• Systemic corticosteroids for axial disease are not supported by evidence 1

Disease-Specific Considerations

Systemic Lupus Erythematosus

• Hydroxychloroquine 200-400 mg daily should be used for all SLE patients unless contraindicated 4
• Photoprotection must be advised to prevent disease flares 1, 4
• Up to 80% of SLE patients are treated with NSAIDs for musculoskeletal symptoms, serositis, and headache, but close monitoring for toxicity is required 2

Systemic Sclerosis

• For Raynaud's phenomenon: cold avoidance, gloves, heating devices, and smoking cessation are mandatory 1, 4
• Nifedipine is first-line pharmacotherapy for Raynaud's, reducing frequency and severity of attacks 1, 4
• Phosphodiesterase-5 inhibitors (sildenafil, tadalafil) for inadequate response to calcium channel blockers 1, 4
• Manual lymph drainage could be considered for puffy hands to improve hand function 1, 4

Polymyositis and Mixed Connective Tissue Disease

• Follow general chronic pain management principles with emphasis on physical activity 1
• Systemic therapies (glucocorticoids, immunosuppressive agents) should be restricted to patients with active systemic disease 1

Gastrointestinal Pain

• Antispasmodics (hyoscyamine, dicyclomine, peppermint oil) are appropriate for GI pain, which affects up to 98% of patients with certain connective tissue diseases 3
• Proton pump inhibitors should be used for gastroesophageal reflux disease in systemic sclerosis 1

Critical Pitfalls to Avoid

• Do not use biological agents (rituximab, anakinra, epratuzumab, abatacept) to treat only musculoskeletal pain, even as rescue therapy—no significant differences versus placebo with fivefold greater economic cost 1
• Do not prescribe opioids as first-line or rescue therapy—recent epidemiological data confirm harm 1
• Do not use repeated NSAIDs or glucocorticoids for chronic, daily non-inflammatory pain 1
• Do not ignore gastrointestinal symptoms—they contribute significantly to overall pain burden and require specific management 3
• Do not delay escalation in secondary Raynaud's phenomenon, as this leads to digital ulcers and poor outcomes 4
• Monitor renal function closely when using NSAIDs in lupus nephritis patients, as they are at increased risk for acute renal failure 2