Painful diabetic peripheral neuropathy

Red Flags

Acute foot ulceration, infection, or new deformity in a diabetic patient with neuropathy — same-day multidisciplinary diabetic foot service; risk of limb loss^[1]
Asymmetric, rapidly progressive, or motor-predominant neuropathy — investigate for non-diabetic cause (CIDP, vasculitis, B12 deficiency, paraproteinaemia, drug toxicity, malignancy)^[1]
Concurrent mood disorder or suicidal ideation — psychiatric assessment alongside pain management; pain and depression compound^[1]
Opioid prescription for diabetic neuropathy — strongly discouraged; review and de-prescribe^[1]

First-line treatment

Interventions

Optimised glycaemic control^[1]
Type 1 DM — intensive control reduces incidence and progression. Type 2 DM — control modestly affects established painful neuropathy; combine with cardio-renal pillar therapy (SGLT2 inhibitor, GLP-1 RA)
Foot care and protective offloading^[1]
Daily foot inspection, well-fitting shoes, avoid walking barefoot, podiatry follow-up; treat pre-ulcer signs urgently
Choose initial agent across four equally effective classes^[1]
TCAs, SNRIs, gabapentinoids, or sodium channel blockers. Selection based on comorbidities, side-effect profile, cost, drug interactions; switch to a different class if inadequate response after 8 weeks at therapeutic dose

First-line drug therapy

Drug	Class	Adult	Paediatric	Notes
Amitriptyline or nortriptyline^[1]	Tricyclic antidepressant	Amitriptyline 10–25 mg PO at night; titrate to 75–150 mg as tolerated. Nortriptyline same range — better tolerated in elderly	—	First-line; useful with comorbid insomnia and depression; cardiac caution in older adults (ECG before higher dose); avoid in glaucoma, prostatic hypertrophy
Duloxetine^[1]	Serotonin-norepinephrine reuptake inhibitor (SNRI)	30 mg PO daily × 1 week then 60 mg daily; max 120 mg in some patients	—	First-line; useful with comorbid depression or anxiety; nausea on initiation, hepatic caution; avoid with MAOI
Venlafaxine extended-release^[1]	SNRI	37.5 mg PO daily; titrate to 150–225 mg/day	—	Alternative SNRI; monitor BP at higher doses
Pregabalin^[1]	Gabapentinoid (α2δ ligand)	75 mg PO BD; titrate to 150–300 mg BD as tolerated	—	First-line; renal dose adjustment; sedation, weight gain, peripheral oedema; concerns about misuse in some jurisdictions
Gabapentin^[1]	Gabapentinoid	300 mg PO night then 300 mg BD then 300 mg TDS over a week; usual 900–3600 mg/day in three divided doses	—	First-line; lower cost than pregabalin; renal dose adjustment; sedation and oedema common
Sodium channel blocker (lacosamide, oxcarbazepine, valproate selected cases)^[1]	Sodium channel blocker	Lacosamide 50 mg PO BD; oxcarbazepine 150 mg PO BD; titrate	—	Alternative class with similar effect size; used when first-line classes fail or are contraindicated; cardiac and hyponatraemia monitoring per agent
Topical capsaicin 8% patch^[1]	TRPV1 agonist (topical)	Single 30-minute application, can repeat every 90 days	—	Localised painful neuropathy; transient burning at application site; pre-treat with topical anaesthetic; specialist application
Topical lidocaine 5% patch^[1]	Sodium channel blocker (topical)	Up to 3 patches applied to most painful area for up to 12 h/24 h	—	Localised pain only; minimal systemic absorption; safer in elderly with comorbidities

Amitriptyline or nortriptyline^[1]

Tricyclic antidepressant

Adult: Amitriptyline 10–25 mg PO at night; titrate to 75–150 mg as tolerated. Nortriptyline same range — better tolerated in elderly
Paediatric: —

First-line; useful with comorbid insomnia and depression; cardiac caution in older adults (ECG before higher dose); avoid in glaucoma, prostatic hypertrophy

Duloxetine^[1]

Serotonin-norepinephrine reuptake inhibitor (SNRI)

Adult: 30 mg PO daily × 1 week then 60 mg daily; max 120 mg in some patients
Paediatric: —

First-line; useful with comorbid depression or anxiety; nausea on initiation, hepatic caution; avoid with MAOI

Venlafaxine extended-release^[1]

SNRI

Adult: 37.5 mg PO daily; titrate to 150–225 mg/day
Paediatric: —

Alternative SNRI; monitor BP at higher doses

Pregabalin^[1]

Gabapentinoid (α2δ ligand)

Adult: 75 mg PO BD; titrate to 150–300 mg BD as tolerated
Paediatric: —

First-line; renal dose adjustment; sedation, weight gain, peripheral oedema; concerns about misuse in some jurisdictions

Gabapentin^[1]

Gabapentinoid

Adult: 300 mg PO night then 300 mg BD then 300 mg TDS over a week; usual 900–3600 mg/day in three divided doses
Paediatric: —

First-line; lower cost than pregabalin; renal dose adjustment; sedation and oedema common

Sodium channel blocker (lacosamide, oxcarbazepine, valproate selected cases)^[1]

Sodium channel blocker

Adult: Lacosamide 50 mg PO BD; oxcarbazepine 150 mg PO BD; titrate
Paediatric: —

Alternative class with similar effect size; used when first-line classes fail or are contraindicated; cardiac and hyponatraemia monitoring per agent

Topical capsaicin 8% patch^[1]

TRPV1 agonist (topical)

Adult: Single 30-minute application, can repeat every 90 days
Paediatric: —

Localised painful neuropathy; transient burning at application site; pre-treat with topical anaesthetic; specialist application

Topical lidocaine 5% patch^[1]

Sodium channel blocker (topical)

Adult: Up to 3 patches applied to most painful area for up to 12 h/24 h
Paediatric: —

Localised pain only; minimal systemic absorption; safer in elderly with comorbidities

Safety-net

Inspect feet daily including soles and between toes; report any blister, callus, or wound the same day — diabetic foot infection can deteriorate within hours^[1]
Avoid alcohol — it worsens neuropathy and interacts with many of the medications used^[1]
Never increase pain medication beyond prescribed dose without speaking to your clinician — many cause sedation and falls in older adults^[1]

Referral criteria

Atypical neuropathy (asymmetric, motor-predominant, rapidly progressive, autonomic-predominant)Neurology and electrophysiology^[1]
Refractory painful diabetic neuropathy after sequential trials of 2–3 different classesPain medicine specialist for adjuncts (high-dose capsaicin, transcutaneous electrical nerve stimulation, spinal cord stimulation in selected cases)^[1]
Diabetic foot ulcer, infection, or Charcot deformityMultidisciplinary diabetic foot team — same-day if active infection or deep ulcer^[1]
Comorbid depression or suicidal ideationMental health and pain medicine coordination^[1]

Clinical summary

Stepwise pharmacologic and non-pharmacologic management of painful diabetic peripheral neuropathy in adults with diabetes.

References

1.AAN/AANEM/AAPMR Practice Guideline Update Summary: Oral and Topical Treatment of Painful Diabetic Polyneuropathy (2022) (2022)