What is the best medication to treat chemotherapy-induced peripheral neuropathy in a patient who has undergone platinum-based (platinum) chemotherapy?

Treatment of Platinum-Based Chemotherapy-Induced Peripheral Neuropathy

Duloxetine is the best medication for treating neuropathy after platinum-based chemotherapy, with the strongest evidence showing it is more effective for platinum-induced neuropathy than for taxane-induced neuropathy. 1

First-Line Treatment: Duloxetine

Start duloxetine at 30 mg daily for the first week, then increase to 60 mg daily for ongoing treatment. 1, 2

• In the pivotal randomized trial of 231 patients with chemotherapy-induced peripheral neuropathy (CIPN), duloxetine reduced average pain by 1.06 points versus 0.34 points with placebo (p=0.003), with 59% of duloxetine patients experiencing pain reduction compared to 38% on placebo 3
• Exploratory subgroup analysis demonstrated duloxetine is significantly more effective for oxaliplatin-induced (platinum) neuropathy than paclitaxel-induced neuropathy 1
• Duloxetine also reduces numbness and tingling symptoms, not just pain 1, 3
• This is the only medication with Level I, Grade B evidence for treating painful CIPN 1

Second-Line Options When Duloxetine Fails or Is Contraindicated

If duloxetine is ineffective after at least 2 weeks at appropriate dosing, or if contraindications exist, consider the following alternatives in order: 1

Anticonvulsants

• Pregabalin or gabapentin can be tried as membrane-stabilizing agents, though evidence is weaker than for duloxetine 1
• One 2020 trial showed pregabalin was superior to duloxetine (93% vs 38% improvement, p<0.001), though this requires confirmation as it contradicts other gabapentinoid trial results 1, 2
• Must be given at appropriate doses for at least 2 weeks before assessing efficacy 1

Tricyclic Antidepressants

• Nortriptyline is a reasonable option based on efficacy in other neuropathic pain conditions, though a small trial (n=51) in cisplatin-treated patients showed no significant benefit 1
• Target maximum dose of 100 mg/day 1

Venlafaxine

• Shown effective in a small randomized trial (n=48) with Level II, Grade C evidence 1
• Can be considered for neuropathic pain treatment, though not as strongly recommended as duloxetine 1

Topical Therapies for Localized Symptoms

Topical Baclofen/Amitriptyline/Ketamine Gel

• Compounded gel containing baclofen 10 mg, amitriptyline 40 mg, and ketamine 20 mg showed improvement on CIPN-20 scores, especially the motor subscale, after 4 weeks 1
• Level II, Grade C evidence 1
• Reasonable to try for selected patients with localized pain, though evidence is limited 1

Other Topical Options

• 1% menthol cream applied twice daily to affected areas and corresponding spinal dermatomal regions improved pain scores after 4-6 weeks (Level III, Grade B) 1
• 8% capsaicin patches have established efficacy for other neuropathic pain forms with one small CIPN study (n=16); effects last 90 days (Level I, Grade C for general neuropathic pain; Level III, Grade C for CIPN) 1
• Topical ketamine 2% and amitriptyline 4% combination showed no benefit in a large trial (n=462) and is not recommended 1

Salvage Options: Opioids

Opioids should only be used as a last resort when other treatments have failed. 1

• Tramadol 200-400 mg in divided doses (extended release formulation preferred) has established efficacy for other neuropathic pain forms with NNT of 4.7 (Level II, Grade C) 1
• Strong opioids at the smallest effective dose may relieve neuropathic pain with NNT of 4.3, but evidence is from non-CIPN neuropathic pain (Level II, Grade C) 1
• No data suggest one opioid is superior to another for painful CIPN 1

Important Caveats and Pitfalls

What NOT to Use

• NSAIDs and glucocorticoids have no supporting data for CIPN treatment 1
• Vitamin B12 is inferior to duloxetine, with direct comparison showing duloxetine significantly more effective for both numbness (p=0.03) and pain (p=0.04) 2
• Acetyl-L-carnitine should be avoided as it may worsen neuropathy over time 1, 2

Prevention Considerations

• No agents are recommended for preventing platinum-induced neuropathy 1, 2
• Calcium/magnesium infusions, venlafaxine, and other preventive strategies lack sufficient evidence or have concerns about reducing chemotherapy efficacy 1
• One 2023 trial showed duloxetine given for 14 days per chemotherapy cycle did not prevent acute oxaliplatin-induced neuropathy, though it reduced distal paresthesia (51% vs 84%, p=0.01) and throat discomfort (37% vs 69%, p=0.01) 4

Timing and Expectations

• Early pain management is of utmost importance to prevent sensitization 1
• Oxaliplatin-induced neuropathy exhibits a "coasting phenomenon" where symptoms worsen for 2-3 months after treatment completion before improving 1, 2
• Approximately 80% of patients experience partial reversibility and 40% complete resolution at 6-8 months post-treatment 1
• All pharmacologic agents should be tried for at least 2 weeks at appropriate doses before switching 1

Quality of Life Impact

• CIPN can markedly affect quality of life and may persist as a debilitating problem for years 1, 2
• Consider dose reduction or chemotherapy modification if intolerable neuropathy develops during active treatment 2, 5

Adjunctive Non-Pharmacological Approaches

• Exercise therapy (home-based muscle strengthening and balance exercises) may provide benefit with significant reduction in neuropathic pain scores (p<0.0001), though larger studies are needed 2
• Acupuncture has insufficient evidence for routine recommendation outside clinical trials 1, 2
• Physical therapy may help address symptoms but is limited by cost, time commitment, and patient motivation 5