What are the medications used to treat peripheral neuropathy?

Medications for Peripheral Neuropathy

For painful peripheral neuropathy, start with either duloxetine 60 mg daily or pregabalin 150 mg daily (divided doses), as these are the only two FDA-approved medications for diabetic neuropathic pain and have the strongest evidence base. 1, 2, 3

First-Line Treatment Options

FDA-Approved Agents (Preferred)

Duloxetine (SNRI):

• Start at 30 mg once daily for one week, then increase to 60 mg once daily 3
• Can increase to maximum 120 mg daily if needed for inadequate response 1, 3
• Number needed to treat (NNT): 5.2 for 60 mg/day, 4.9 for 120 mg/day 4
• Advantages: fewer anticholinergic effects than tricyclics, no ECG monitoring required, once-daily dosing 5
• Common side effects: nausea (minimize by starting at 30 mg), somnolence, dizziness 3

Pregabalin (Anticonvulsant):

• Start at 150 mg/day in divided doses (50 mg three times daily or 75 mg twice daily) 1, 2
• Increase to 300 mg/day within one week based on response 1, 2
• Maximum dose: 600 mg/day 1, 2
• NNT: 5.99 for 300 mg/day, 4.04 for 600 mg/day 4
• Critical dosing principle: Many patients who fail lower doses will respond when escalated to higher doses 6
• Use "asymmetric dosing" with larger evening dose to minimize daytime sedation 7

Alternative First-Line Agents

Tricyclic Antidepressants (TCAs):

• Amitriptyline or imipramine: 25-75 mg/day 1
• Start at 10 mg/day in older patients, titrate slowly to maximum 75 mg/day 1
• NNT: 1.5-3.5 (though based on smaller crossover trials) 1
• Critical safety concern: doses >100 mg/day associated with increased sudden cardiac death risk 1
• Obtain ECG before starting in patients >40 years or with cardiac disease; avoid if PR or QTc prolongation present 1, 5
• Side effects limit use: anticholinergic effects (dry mouth, constipation, urinary retention), orthostatic hypotension, drowsiness 1, 5

Gabapentin:

• Start 100-300 mg at bedtime or three times daily 1, 4
• Titrate to 900-3600 mg/day in divided doses 1, 4
• Less predictable absorption than pregabalin; requires dose adjustment in renal impairment 5

Venlafaxine (SNRI):

• 150-225 mg/day 1
• Alternative to duloxetine but lacks FDA approval for neuropathic pain 1

Second-Line Treatment Options

Opioids (Reserve for Refractory Cases):

• Tramadol: 200-400 mg/day in divided doses 1
• Dual mechanism: weak μ-opioid agonist plus serotonin/norepinephrine reuptake inhibition 1, 5
• Lower abuse potential than strong opioids 5
• Oxycodone: 20-80 mg/day 1
• Morphine sulfate sustained-release: 20-80 mg/day 1
• Use smallest effective dose; neuropathic pain is generally less opioid-responsive 5

Topical Agents (For Localized Pain)

Capsaicin cream (0.075%):

• Apply sparingly 3-4 times daily 1
• Useful for localized peripheral neuropathic pain 1, 5

5% Lidocaine patches:

• Apply daily to painful area 5
• Minimal systemic absorption, preferred in older adults 5

Treatment Algorithm

Step 1: Initial Treatment

• Choose duloxetine 60 mg daily OR pregabalin 150 mg/day based on patient factors 1, 4, 5
• In older adults or those with cardiac disease, prefer duloxetine or gabapentin over TCAs 1, 5
• Assess response after 2-4 weeks; treatment successful if ≥30% pain reduction from baseline 4

Step 2: Inadequate Response to Initial Dose

• For pregabalin: escalate to 300 mg/day, then 450 mg/day, then 600 mg/day as needed 6, 7
• For duloxetine: increase to 120 mg/day 1, 3
• Many patients require higher doses for optimal benefit 6

Step 3: Partial Response to First-Line Agent

• Add medication from different class (e.g., add gabapentin to duloxetine) 5
• Combination therapy may provide superior pain relief 5

Step 4: Failed First-Line Monotherapy and Combination

• Switch to alternative first-line agent from different class 5
• Consider tramadol or referral to pain specialist 5

Critical Pitfalls to Avoid

Underdosing pregabalin:

• Patients often remain on suboptimal doses (150-300 mg/day) when they would respond to 450-600 mg/day 6, 7
• Use "low and slow" titration to minimize side effects, but don't stop at inadequate doses 7

Premature TCA use in high-risk patients:

• Always screen for cardiac disease and obtain ECG in patients >40 years before prescribing TCAs 1, 5
• Avoid in patients with orthostatic hypotension, urinary retention, or constipation 1

Expecting disease modification:

• All pharmacologic treatments are purely symptomatic; none alter the progressive nerve fiber loss 1
• Exception: tight glycemic control in diabetic neuropathy may slow progression 1

Using opioids as first-line:

• Reserve for refractory cases after first-line agents have failed 5
• Risk of dependence, cognitive impairment, and pronociception 5

Special Populations

Older adults:

• Start TCAs at 10 mg/day maximum, increase slowly 1
• Prefer topical agents (lidocaine, capsaicin) due to minimal systemic effects 5
• Lower initial doses of all systemic agents with slower titration 4, 5

Renal impairment:

• Adjust gabapentin and pregabalin doses based on creatinine clearance 5

Cardiac disease:

• Avoid TCAs or limit to <100 mg/day with ECG monitoring 1, 5
• Prefer duloxetine, pregabalin, or gabapentin 1, 5