What is the recommended treatment for Raynaud’s phenomenon, including non‑pharmacologic measures and first‑ and second‑line medications?

Treatment of Raynaud's Phenomenon

Begin with trigger avoidance and lifestyle modifications for all patients, then prescribe extended-release nifedipine 30 mg daily (titrated to 60–90 mg) as first-line pharmacotherapy; escalate to phosphodiesterase-5 inhibitors (sildenafil or tadalafil) if calcium-channel blockers fail, and reserve intravenous iloprost for severe refractory disease. 1, 2

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Non-Pharmacological Management (Mandatory First Step)

All patients must implement trigger avoidance before or alongside any medication. 2, 3

Cold Protection

• Wear insulated mittens (not gloves), warm footwear, hats, and coats in cold environments 1, 3
• Use chemical hand and foot warmers during cold exposure 1, 3
• Ceramic-impregnated gloves may provide modest benefit, though evidence is limited 3

Lifestyle Modifications

• Smoking cessation is mandatory—tobacco directly worsens vasospasm and undermines all therapies 2, 3
• Discontinue vasoconstrictive medications: beta-blockers, ergot alkaloids, bleomycin, and clonidine 1, 2, 3
• Implement stress-reduction techniques, as emotional stress triggers attacks 2, 3
• Avoid occupational vibration injury and repetitive hand trauma 2, 3

Physical Therapy

• Structured exercises to stimulate peripheral blood flow and generate heat reduce attack frequency 1, 3
• In connective-tissue disease with hand edema, five weekly sessions of manual lymphatic drainage improve hand function 3

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Pharmacological Treatment Algorithm

First-Line: Calcium-Channel Blockers

Extended-release nifedipine is the gold-standard first-line agent for both primary and secondary Raynaud's. 1, 2

Dosing Protocol

• Start nifedipine extended-release 30 mg once daily on an empty stomach 1
• Titrate over 7–14 days to a target of 60–90 mg daily based on therapeutic response and tolerability 1
• At each titration step, assess frequency, duration, and severity of attacks 1

Efficacy

• Meta-analyses demonstrate that nifedipine reduces attack frequency and severity in approximately two-thirds of patients 1, 2
• If nifedipine is not tolerated, alternative dihydropyridines (felodipine, isradipine) or diltiazem may be used, though efficacy may be modestly lower 3

Critical Safety Warnings

• Immediate-release nifedipine must not be used without concurrent beta-blocker therapy in acute coronary syndromes—omission is associated with increased mortality 1
• Nifedipine is contraindicated in clinically significant left-ventricular dysfunction or high risk of cardiogenic shock 1
• Common adverse effects include hypotension, peripheral edema, headache, and flushing 4

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Second-Line: Phosphodiesterase-5 Inhibitors

When calcium-channel blockers provide inadequate response, add or switch to sildenafil or tadalafil. 1, 2, 3

Indications

• Inadequate symptom control despite optimized nifedipine dosing 1, 2
• Presence of digital ulcers—PDE5 inhibitors promote both healing and prevention 1, 2

Efficacy

• Effectively reduce frequency, duration, and severity of attacks 1, 2
• Mixed but generally positive results for digital ulcer prevention 1, 2

Practical Considerations

• Cost and off-label status may limit utilization 1, 3

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Third-Line: Intravenous Prostacyclin Analogue (Iloprost)

For severe Raynaud's refractory to oral therapies, intravenous iloprost is the recommended escalation. 1, 2, 3

Indications

• Severe, frequent attacks despite calcium-channel blockers and PDE5 inhibitors 1, 2
• Non-healing digital ulcers 1, 2

Efficacy

• Proven to reduce attack frequency and severity 1, 3
• Particularly effective for healing existing digital ulcers 1, 2, 3

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Management of Digital Ulcers

Prevention of New Ulcers

Bosentan (endothelin-receptor antagonist) is the most effective agent for preventing new digital ulcers in systemic sclerosis. 1, 2, 3

Dosing

• Start bosentan 62.5 mg twice daily for 4 weeks, then increase to 125 mg twice daily 1
• Most effective in patients with ≥4 digital ulcers at baseline 1

Important Limitation

• Bosentan prevents new ulcers but does not promote healing of existing ulcers 1, 4

Alternative Prevention Strategies

• PDE5 inhibitors also contribute to ulcer prevention, though results are mixed 1, 2

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Healing of Existing Ulcers

Intravenous iloprost and PDE5 inhibitors both promote healing of established digital ulcers. 1, 2, 3

Wound Care Essentials

• Specialized wound-care teams should manage ulcer care 1
• Reserve antibiotics for suspected infection only 1
• Provide adequate analgesia—ulcer pain is often severe 1, 5
• Soap-and-water washes with damp dressings or silver sulfadiazine cream 6

Ancillary Therapy

• Topical nitroglycerin may provide relief for acute painful episodes 1, 3

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Severity-Based Treatment Pathway

Mild Raynaud's

• Non-pharmacological measures alone 3
• Add nifedipine if quality of life is impaired 3

Moderate to Severe Raynaud's or Inadequate Response to Calcium-Channel Blockers

• Introduce or switch to PDE5 inhibitor (sildenafil or tadalafil) 1, 3

Severe Refractory Disease

• Consider intravenous iloprost 1, 3

Presence of Digital Ulcers

• Use bosentan for prevention 1, 3
• Use intravenous iloprost or PDE5 inhibitors for healing 1, 3

Gangrene or Osteomyelitis

• Amputation may be required in extreme cases 1
• Fingertip amputation provides excellent pain relief and generally heals with time 6

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Interventional Approaches for Refractory Disease

• Digital sympathectomy may be employed for persistent ulcer-related problems 1, 3
• Emerging therapies such as botulinum-toxin injections or autologous fat grafting show promise for ulcer healing and prevention 1, 3
• Cervicodorsal sympathectomy is not recommended for upper extremity symptoms 7
• Lumbosacral sympathectomy may cure vasospastic attacks of the toes 7

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Critical Pitfalls to Avoid

Always Screen for Secondary Causes

Raynaud's is present in nearly all systemic sclerosis patients and often represents the initial manifestation. 3

Red-Flag Features Requiring Urgent Assessment

• Severe painful episodes with digital ulceration or tissue necrosis 3
• Systemic symptoms: joint pain, skin changes, dysphagia, weight loss, fever 3
• Involvement of the entire hand rather than isolated digits 3
• Onset after age 60 (suggests possible atherosclerotic disease) 3

Recommended Laboratory Workup for Suspected Secondary Raynaud's

• Complete blood count with differential 1, 3
• Erythrocyte sedimentation rate 1, 3
• Antinuclear antibody panel 1, 3
• Rheumatoid factor 1, 3
• Anticentromere and anti-Scl-70 antibodies 1, 3
• Anticardiolipin antibodies and lupus anticoagulant 1, 3
• Ankle-brachial index to exclude peripheral arterial disease 1

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Do Not Continue Triggering Medications

Continuing beta-blockers, ergot alkaloids, bleomycin, or clonidine will undermine all treatment efforts. 2, 3

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Do Not Delay Escalation in Secondary Raynaud's

Delayed diagnosis and treatment of connective-tissue-disease-associated Raynaud's leads to digital ulcers and poor outcomes. 2

• Early referral to rheumatology is critical when secondary causes are suspected 1
• Rheumatologists achieve superior outcomes: earlier diagnosis, more frequent disease-modifying therapy, better prevention of joint damage, and preservation of physical function 1
• Avoiding referral delays when red-flag features are present is the most significant preventable cause of poor outcomes 1

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Alternative Therapies with Limited Evidence

• Fluoxetine (selective serotonin reuptake inhibitor) may be considered for refractory attacks, but evidence is limited to small studies 1, 3
• Acupuncture does not demonstrate reliable therapeutic effect 3
• Biofeedback training has insufficient evidence to support routine use 3, 7
• Ginkgo biloba yields inconsistent results and cannot be recommended 3
• L-arginine supplementation lacks robust supporting data 3
• Antioxidant therapies have produced inconclusive outcomes 3