What is the likely cause of nocturnal burning pain in the feet and hands of a 56-year-old woman with diabetes and an HbA1c of approximately 53 mmol/mol?

Diabetic Small Fiber Neuropathy

This is diabetic small fiber neuropathy causing painful neuropathic symptoms, characterized by the classic nocturnal burning pain in a distal, symmetrical distribution affecting both feet and hands. 1, 2

Why This Diagnosis Fits

The clinical presentation is pathognomonic for small fiber neuropathy in diabetes:

• Burning pain is the hallmark symptom of small fiber (C-fiber and Aδ-fiber) damage, which constitutes 79.6–91.4% of peripheral nerve fibers 1
• Nocturnal exacerbation is a classic diagnostic feature caused by spontaneous ectopic nerve firing that becomes more noticeable when external distractions are minimal at night 1, 2
• Distal symmetrical involvement (both feet and hands) is the typical pattern of diabetic sensorimotor polyneuropathy 1
• The HbA1c of 53 mmol/mol (approximately 7.0%) indicates suboptimal glycemic control that directly contributes to neuropathy progression 1, 3

Pathophysiology Driving Her Symptoms

Small fiber damage produces burning sensations through multiple mechanisms 2, 4:

• Changes in sodium and calcium channel distribution create spontaneous, ectopic nerve firing 2
• Peripheral sensitization causes heightened responsiveness of pain neurons 2
• Central sensitization amplifies pain signals in the spinal cord when external distractions are minimal at night 2
• Blood glucose instability directly contributes to neuropathic pain generation 2

Immediate Management Priorities

Step 1: Initiate First-Line Neuropathic Pain Treatment

Start pregabalin 75 mg at bedtime immediately, then increase to 150 mg at bedtime after one week if tolerated 3. The effective therapeutic range is 300 mg/day total (150 mg twice daily), with a number-needed-to-treat of 4.0–5.9 for ≥50% pain reduction 3. Do not exceed 300 mg/day because higher doses provide no additional analgesic benefit and markedly worsen tolerability 3.

Alternative first-line option if pregabalin is not tolerated: duloxetine 60 mg once daily (NNT 4.9–5.2), which has the added benefit of treating comorbid depression present in over two-thirds of patients with painful diabetic neuropathy 3, 2. Avoid duloxetine if she has any hepatic disease 3.

Step 2: Optimize Glycemic Control to Slow Progression

Target HbA1c of 6–7% to prevent further neuropathy progression, though this will not reverse existing nerve damage 1, 3. Her current HbA1c of 53 mmol/mol (7.0%) is acceptable but could be improved 1. Glycemic control effectively prevents diabetic peripheral neuropathy in type 1 diabetes and modestly slows progression in type 2 diabetes 1.

Step 3: Screen for Reversible Causes

Check vitamin B12 level immediately, especially if she is on metformin, as deficiency can cause or worsen neuropathic symptoms 1, 3. Also screen for hypothyroidism (TSH), renal disease (creatinine), and review medications for neurotoxic agents 1, 3.

Step 4: Assess for Loss of Protective Sensation

Perform 10-g monofilament testing and 128-Hz tuning fork vibration testing to detect loss of protective sensation, which predicts foot ulcer and amputation risk even when pain symptoms are controlled 1, 3. Up to 50% of diabetic peripheral neuropathy is asymptomatic but still increases ulceration risk 1.

Clinical Tests to Perform Now

• Small-fiber function: pinprick and temperature sensation 1
• Large-fiber function: lower-extremity reflexes, vibration perception with 128-Hz tuning fork, and 10-g monofilament 1
• Visual foot inspection for deformities, callus formation, and skin changes 1, 3

Electrophysiological testing is not needed unless clinical features are atypical or the diagnosis is uncertain, as nerve conduction studies assess large myelinated fibers and may be normal in pure small fiber neuropathy 1.

Addressing Sleep Disturbance and Mood

Screen for depression and anxiety using validated tools, as over two-thirds of patients with painful diabetic neuropathy develop these comorbidities, which worsen pain outcomes and quality of life 3, 2. Initial neuropathic pain treatment should concurrently address sleep and mood disturbances 3.

Critical Pitfalls to Avoid

• Do not dismiss nocturnal symptoms as insignificant—they represent a classic diagnostic feature requiring treatment 2
• Do not prescribe opioids (including tramadol or tapentadol) for chronic diabetic neuropathic pain due to addiction risk, adverse events, and lack of long-term efficacy 1, 3
• Do not advise prolonged cold water immersion or ice application for symptom relief, as this can lead to skin ulceration and infection 2
• Do not neglect foot examination—perform annual comprehensive assessment even when pain is controlled, as loss of protective sensation can be asymptomatic 1, 3

If First-Line Treatment Fails

If pregabalin at 300 mg/day provides insufficient relief after 4–6 weeks, add duloxetine 60 mg daily as combination therapy rather than escalating pregabalin dose 3. Low-dose combination therapy (pregabalin + duloxetine) provides greater pain relief than dose escalation of a single agent with fewer adverse effects 3.

Second-line options include tricyclic antidepressants (amitriptyline 25–75 mg at bedtime), but avoid in patients ≥65 years or with glaucoma, orthostatic hypotension, or cardiovascular disease 3. Third-line options include sodium-channel blockers (carbamazepine, lamotrigine) 3.

When to Refer

Refer to neurology or pain specialist when pain remains inadequately controlled after trials of at least two first-line medications at therapeutic doses, or when clinical features are atypical 1, 3.