Rest pain in the limbs

Rest pain is persistent limb pain present without exertion. It is classically a burning or aching pain in the forefoot and toes (or fingers), worse at night and in bed, and relieved by hanging the leg over the side of the bed or sitting up.

It signals critical limb ischaemia (chronic limb threatening ischaemia) until proved otherwise. It also has neuropathic, musculoskeletal, inflammatory and infective causes.

Clinical relevance. Chronic limb threatening ischaemia carries a major amputation rate of 25% to 40% at one year without revascularisation and a one year mortality of 20% to 25%. Rapid diagnosis and revascularisation save limbs. The main pitfall is misattributing nocturnal foot pain to neuropathy, arthritis, cramp or restless legs.

Classification.

• Ischaemic: chronic limb threatening ischaemia (rest pain with or without ulcer or gangrene; Rutherford category 4 to 6; Fontaine III and IV), acute on chronic ischaemia, embolic ischaemia, vasculitis, Buerger disease, severe vasospasm, atheroembolism, thrombosis of a bypass graft.
• Neuropathic: diabetic painful neuropathy, small fibre neuropathy, alcohol, vitamin B12 deficiency, chemotherapy, HIV, leprosy, erythromelalgia, complex regional pain syndrome, nerve entrapment (tarsal tunnel), radiculopathy.
• Musculoskeletal and inflammatory: gout, osteomyelitis, septic arthritis, Charcot foot, stress fracture, plantar fasciitis, inflammatory arthritis, osteonecrosis, tumour, bone metastasis.
• Compressive and spinal: cauda equina syndrome, lumbar spinal stenosis, sciatica, nerve root compression, thoracic outlet syndrome (upper limb), cervical radiculopathy.
• Venous: venous ulcer and severe venous disease, deep vein thrombosis, phlegmasia.

Definition of chronic limb threatening ischaemia. Rest pain for over 2 weeks, with ankle pressure under 50 mmHg, toe pressure under 30 mmHg, or transcutaneous oxygen under 30 mmHg; or ulcer or gangrene attributable to arterial disease.

History.

• Pain: site (forefoot, toes, heel, whole foot), character (burning, aching, boring), timing (nocturnal, wakes from sleep, worse lying flat), relief (dangling leg, walking around, sleeping in a chair), duration, progression, intermittent claudication history, previous revascularisation.
• Tissue: ulcers, black toes, infection, discolouration, slow healing, minor trauma.
• Risk factors: smoking, diabetes, hypertension, hyperlipidaemia, kidney disease, atrial fibrillation, previous stroke or coronary disease, vasculitis, family history, drugs (ergots).
• Neuropathic features: burning, shooting, allodynia, glove and stocking distribution, loss of sensation, alcohol, B12, diabetes duration.
• Spinal features: back pain, bilateral symptoms, saddle numbness, bladder and bowel disturbance, weakness.
• Gout or arthritis, joint swelling, fever, trauma, steroid use.
• Systemic: weight loss, fever, night sweats, cough, haemoptysis.
• Social: footwear, hygiene, mobility, falls, home support, smoking.

Examination.

• Vital signs, temperature, rhythm, blood pressure in both arms.
• Skin: pallor on elevation and rubor on dependency, cold shiny hairless skin, atrophic nails, ulcers (punched out, painful, at toes and heel, pressure points), gangrene (dry or wet), cellulitis, abscess, maceration between toes.
• Pulses and Doppler signals (femoral, popliteal, pedal), capillary refill, bruits, aneurysm.
• Neurological: sensation (monofilament, vibration, pin prick), reflexes, power, gait, ankle jerks, signs of cauda equina.
• Musculoskeletal: joints, bony tenderness, deformity (Charcot), tendons, plantar fascia; probe to bone for ulcers.
• Venous disease: varicosities, oedema, venous eczema, ulcer at medial malleolus.
• Upper limb: similar assessment, thoracic outlet signs.

Red flags.

• Rest pain with ulcer, gangrene or infection (chronic limb threatening ischaemia).
• Sudden onset cold, pale, painful limb or neurological deficit (acute limb ischaemia).
• Wet gangrene, spreading infection, fever, sepsis, crepitus (necrotising infection).
• Probe to bone ulcer or sinus (osteomyelitis).
• Back pain with saddle numbness, bladder and bowel dysfunction, or bilateral leg weakness (cauda equina).
• Pulseless pulsatile mass (aneurysm with thrombosis).
• Unilateral swelling, cyanosis (phlegmasia).
• Rapidly progressive pain in a smoker under 50 (Buerger disease).

Ischaemic. Chronic limb threatening ischaemia from atherosclerosis (multilevel disease), acute on chronic thrombosis, embolism, graft occlusion, popliteal aneurysm thrombosis, Buerger disease, vasculitis (polyarteritis nodosa, giant cell arteritis, Takayasu, systemic lupus erythematosus, scleroderma), atheroembolism, hypercoagulable states, antiphospholipid syndrome, Raynaud phenomenon with critical digital ischaemia, ergotism.

Neuropathic. Painful diabetic peripheral neuropathy, small fibre neuropathy, alcoholic neuropathy, vitamin B12 deficiency, chemotherapy induced neuropathy, HIV neuropathy, leprosy, hereditary neuropathy, erythromelalgia, complex regional pain syndrome, Morton neuroma, tarsal tunnel syndrome, lumbosacral radiculopathy.

Infective and inflammatory. Osteomyelitis (including diabetic foot), cellulitis, septic arthritis, gout, pseudogout, inflammatory arthritis, plantar fasciitis, bursitis, Charcot neuroarthropathy.

Musculoskeletal and spinal. Lumbar spinal stenosis, disc herniation, cauda equina syndrome, stress fracture, osteonecrosis, bone tumour or metastasis, tendinopathy.

Venous. Venous ulcer, chronic venous insufficiency, deep vein thrombosis, restless legs syndrome, nocturnal cramps.

1. Palpate pulses and use a hand held Doppler. Measure ankle brachial pressure index (0.4 or under, or ankle systolic pressure under 50 mmHg, indicates critical ischaemia), toe pressure (under 30 mmHg) and toe brachial index. In calcified vessels (diabetes, kidney disease) rely on toe pressure, pulse volume recordings and transcutaneous oxygen pressure (under 30 mmHg).
2. Duplex ultrasound of the arterial tree, then CT angiography or MR angiography (or digital subtraction angiography with endovascular treatment planned). Include inflow (aortoiliac) and outflow (tibial and pedal) vessels.
3. Blood tests: full blood count, ESR, C reactive protein, urea, creatinine, electrolytes, glucose and HbA1c, lipids, liver function, coagulation screen, and urate. Add blood cultures for infection, thrombophilia and antiphospholipid antibodies in young patients, and vasculitis serology (antinuclear antibody, antineutrophil cytoplasmic antibody, complement).
4. Wound assessment: swab after debridement and bone biopsy for suspected osteomyelitis. Plain radiograph, MRI or white cell scintigraphy for bone infection or Charcot disease.
5. Neurological assessment: monofilament, vibration threshold, nerve conduction studies, B12, folate, thyroid stimulating hormone, alcohol history, HIV test, serum protein electrophoresis, glucose tolerance.
6. Spinal imaging (MRI) when features suggest spinal stenosis or cauda equina compression, urgent if red flags.
7. ECG and echocardiography to identify an embolic source; coronary risk assessment before intervention.
8. Joint aspiration for suspected septic arthritis or gout.
9. Venous duplex for suspected thrombosis.

Limits. In diabetes and kidney disease the index may be falsely normal; toe pressures are needed. Neuropathy and ischaemia often coexist in the diabetic foot. Absent pulses do not alone prove critical ischaemia. Imaging contrast carries a risk of kidney injury.

Immediate assessment of ischaemia severity and limb viability. Classify as viable, marginally threatened or immediately threatened (Rutherford: sensory loss, motor weakness, absent arterial and venous Doppler signals mean immediately threatened). Marginal or immediate threat: urgent vascular surgery assessment the same day.

Analgesia.

Paracetamol 1 g every 6 hours (maximum 4 g, 3 g if frail or under 50 kg).

Add opioid for severe pain: morphine sulphate immediate release 5 to 10 mg orally every 4 hours, or oxycodone 5 mg every 4 to 6 hours, with laxatives (senna 15 mg at night, macrogol 1 to 2 sachets daily).

Neuropathic component, one of these options:

• Gabapentin 300 mg at night increased every 3 days to 300 to 600 mg three times daily (maximum 3.6 g daily; adjust for renal function).
• Pregabalin 75 mg twice daily increasing to 150 mg twice daily (maximum 600 mg daily).
• Amitriptyline 10 to 25 mg at night increasing to 75 mg.

Sleep with the foot of the bed raised slightly on blocks or in a chair, but not raised higher than the heart (elevation worsens ischaemic pain).

Avoid NSAIDs when kidney function is poor or bleeding risk is high. Epidural or regional block in refractory pain.

Revascularisation (the definitive treatment for ischaemic rest pain).

Options are endovascular angioplasty with or without stenting, or open surgical bypass (autologous vein preferred). The multidisciplinary vascular team chooses on the basis of anatomy, comorbidity and life expectancy. Revascularise within days. Hybrid procedures are also used. Amputation (transtibial or transfemoral) is for non salvageable limbs, overwhelming sepsis or uncontrolled pain, with rehabilitation and prosthetic assessment.

For acute on chronic thrombosis: unfractionated heparin bolus 5,000 units then infusion 18 units/kg/hour and catheter directed thrombolysis or thrombectomy.

Medical therapy (all patients).

• Antiplatelet therapy: aspirin 75 mg daily or clopidogrel 75 mg daily. After endovascular intervention add clopidogrel 75 mg for 1 to 3 months. Consider rivaroxaban 2.5 mg twice daily plus aspirin 100 mg.
• High intensity statin: atorvastatin 40 to 80 mg daily; LDL cholesterol under 1.4 mmol/L with ezetimibe 10 mg as needed.
• Blood pressure under 130/80 mmHg (ramipril 2.5 to 10 mg daily and amlodipine 5 to 10 mg daily).
• Diabetes control; smoking cessation (nicotine replacement, varenicline, bupropion); weight loss; exercise when pain permits.
• Prostanoids: iloprost intravenously 0.5 to 2 nanograms/kg/minute for 6 hours daily for 14 to 28 days in patients who cannot be revascularised.
• Spinal cord stimulation; sympathectomy in selected cases; gene and cell therapy are investigational.

Wound and infection management.

• Debride necrotic tissue only after perfusion is restored or the plan agreed (dry gangrene is left to demarcate). Pressure offloading; moist wound dressings; negative pressure therapy after revascularisation.
• Mild (superficial) infection: flucloxacillin 500 mg to 1 g four times daily or doxycycline 100 mg twice daily for 7 days.
• Moderate to severe or diabetic infection: amoxicillin with clavulanic acid 625 mg three times daily orally or 1.2 g three times daily intravenously, or ceftriaxone 2 g daily plus metronidazole 500 mg every 8 hours, or piperacillin-tazobactam 4.5 g every 6 hours.
• Add vancomycin 15 to 20 mg/kg every 8 to 12 hours if MRSA risk.
• Osteomyelitis: 6 weeks after surgical debridement (shorter if resected). Drain abscesses and debride urgently.
• Tetanus prophylaxis; glucose control; nutrition (protein 1.2 to 1.5 g/kg, vitamin D, zinc if deficient).

Non ischaemic causes.

• Neuropathic: glucose control, pain agents (gabapentin, pregabalin, amitriptyline), topical capsaicin 0.075% cream or lidocaine 5% plaster, duloxetine 30 mg daily increasing to 60 mg daily. Replace B12 (hydroxocobalamin 1 mg intramuscularly three times weekly for 2 weeks then every 3 months). Stop alcohol; foot protection.
• Gout: colchicine 500 micrograms twice daily to three times daily, or naproxen 500 mg twice daily with a proton pump inhibitor, or prednisolone 30 to 40 mg daily for 5 days. Start allopurinol 100 mg daily (titrate to urate under 360 micromol/L) after the flare.
• Cauda equina: urgent MRI and neurosurgical decompression.
• Complex regional pain syndrome: physiotherapy, prednisolone 30 mg daily for 2 weeks, bisphosphonate, pain team.
• Charcot foot: total contact casting and non weight bearing.
• Restless legs syndrome: treat iron deficiency (ferrous sulphate 200 mg daily if ferritin under 75 micrograms/L), pramipexole 0.125 mg at night or gabapentin.

Foot care. Daily inspection, moisturise, protective footwear, avoid barefoot walking and heat, podiatry, never use compression bandages in arterial ischaemia without vascular approval.

Monitoring. Review pain and wounds weekly. Vascular follow up with duplex at 1, 6 and 12 months after intervention. Renal function after contrast; lipids, HbA1c, blood pressure; annual foot checks; assess the contralateral limb.

Referral and escalation. Immediate vascular surgery referral for suspected chronic limb threatening ischaemia. Involve a multidisciplinary limb salvage team including endovascular specialist, diabetologist, podiatrist, microbiologist, orthopaedic and plastic surgeon. Neurosurgery for cauda equina; rheumatology for vasculitis; pain team; palliative care for patients who cannot be revascularised.

Admission. Rest pain with tissue loss, infection or sepsis, acute on chronic ischaemia, uncontrolled pain, cauda equina syndrome, severe comorbidity, or need for urgent revascularisation.

Safety netting. Return urgently for a cold, pale, blue or numb foot, new black toes, spreading redness, swelling, fever, pus, uncontrolled pain, loss of bladder or bowel control, or saddle numbness. Never apply hot water bottles or heat pads.

Special groups. Diabetes: ischaemia, neuropathy and infection coexist; examine feet at every visit and refer early. Older adults: atypical presentations, falls, frailty and need for shared decisions about amputation versus palliation. Kidney disease: contrast kidney injury; calcified vessels. Young patients: Buerger disease, thrombophilia, vasculitis, popliteal entrapment, and drug use. Pregnancy: antithrombotic choices need specialist advice.

Endemic regions: late presentation with gangrene, leprosy, HIV related vasculopathy, tuberculosis of bone, and delayed access to angioplasty make amputation common.