What are the treatment options for an adult patient with colorectal cancer on FOLFIRI (fluorouracil, oxaliplatin, leucovorin, irinotecan) chemotherapy with neuropathy, currently being treated with Lyrica (pregabalin) 150mg twice daily?

Management of Neuropathy in a Patient on FOLFIRI Currently Taking Pregabalin 150mg BID

Switch from pregabalin to duloxetine 60mg daily as first-line therapy, as duloxetine is the only agent with a positive recommendation from ASCO for treating established chemotherapy-induced peripheral neuropathy (CIPN), while pregabalin has failed to demonstrate benefit in multiple randomized trials for CIPN. 1, 2

Critical Context: FOLFIRI and Neuropathy

FOLFIRI (irinotecan-based chemotherapy) typically causes less severe neuropathy compared to oxaliplatin-containing regimens like FOLFOX. 1 However, there are case reports suggesting that switching from oxaliplatin-based therapy (mFOLFOX6) to FOLFIRI can paradoxically augment pre-existing peripheral neuropathy, though the mechanism remains unclear. 3 If this patient previously received oxaliplatin, the current neuropathy may represent residual oxaliplatin-induced damage rather than FOLFIRI-related toxicity. 1

Why Pregabalin is Inadequate

Your current pregabalin regimen lacks evidence-based support for CIPN. 1, 2

• Multiple randomized placebo-controlled trials have demonstrated that pregabalin does not prevent or effectively treat chemotherapy-induced neuropathy, including studies in both paclitaxel and oxaliplatin settings. 1
• One trial in oxaliplatin-treated colorectal cancer patients (N=143) showed preemptive pregabalin did not decrease chronic pain or improve quality of life. 1
• Another pregabalin trial was terminated early due to lack of efficacy. 1
• ASCO has weakened its support for gabapentinoids compared to previous guidelines, making them harder to endorse for cancer-related neuropathy. 1, 2

Evidence-Based Treatment Algorithm

First-Line: Duloxetine

Initiate duloxetine 30mg daily for one week, then increase to 60mg daily (target dose 60-120mg/day). 1, 2

• Duloxetine is the only agent with a positive ASCO recommendation for treating established CIPN, based on a randomized controlled trial of 231 patients with chemotherapy-induced neuropathic pain. 1, 2
• This represents the strongest and most recent evidence available for CIPN treatment. 1, 2

Second-Line: Tricyclic Antidepressants

If duloxetine fails or is not tolerated, add or switch to nortriptyline or desipramine (preferred over amitriptyline due to better side effect profile). 1, 2

• While limited CIPN-specific evidence exists, tricyclic antidepressants demonstrate efficacy in other neuropathic conditions and are reasonable to try. 1, 2
• However, current enthusiasm for tricyclics has waned due to lack of positive randomized trials specifically for CIPN and unfavorable side effects. 1

Third-Line: Gabapentinoids (Only After Duloxetine Failure)

If duloxetine ± tricyclic antidepressant fails, consider gabapentin 1800-3600mg/day divided three times daily, but inform the patient about limited evidence. 1, 2

• The target dose must be 1800-3600mg/day for neuropathic pain efficacy; inadequate dosing (<1800mg/day) is the most common error explaining treatment failures. 2
• Start gabapentin 300mg once daily, increase by 300mg every 3-7 days until reaching minimum 1800mg/day. 2
• Some insurance companies require gabapentinoid trial before approving duloxetine, which is not evidence-based. 1
• Adjust doses for renal impairment as gabapentin is renally cleared. 2

Critical Pitfalls to Avoid

Do not continue pregabalin at current dose expecting benefit. 1

• Your patient is on pregabalin 150mg BID (300mg/day total), which is within the FDA-approved range for neuropathic pain (150-600mg/day). 4
• However, even at maximum doses (600mg/day), pregabalin has not demonstrated efficacy for CIPN in controlled trials. 1
• The FDA label indicates that patients not experiencing sufficient pain relief at 300mg/day may increase to 600mg/day, but this is for diabetic neuropathy and postherpetic neuralgia, not CIPN. 4

Do not use inadequate gabapentin doses if you choose to trial it. 2

• Historical reports of low-dose gabapentin (100mg BID-TID) for oxaliplatin neuropathy are not biologically plausible given target doses of 1800-3600mg/day. 1
• One randomized trial showed no benefit for gabapentin in treating established CIPN. 1

Additional Considerations

Topical Therapies

Consider topical treatments as adjunctive therapy, though evidence is limited. 1

• A topical gel containing baclofen, amitriptyline, and ketamine showed promise in one trial, but enthusiasm has waned due to lack of FDA-approved products (requires compounding) and a subsequent negative trial of amitriptyline/ketamine without baclofen. 1
• Topical lidocaine 5% patches have minimal systemic absorption and may be safer, particularly in patients with renal impairment. 5

Multimodal Approach

Combining duloxetine with non-pharmacologic interventions may provide additional benefit. 1

• While preliminary evidence suggests potential benefit from exercise, acupuncture, and scrambler therapy, larger definitive studies are needed to confirm efficacy. 1

Monitoring Chemotherapy Continuation

Assess whether neuropathy severity warrants FOLFIRI dose modification or discontinuation. 1

• Neuropathy can limit chemotherapy delivery and potentially affect cancer outcomes. 1
• Unlike oxaliplatin (which should be discontinued after 3-4 months to prevent cumulative neurotoxicity), irinotecan in FOLFIRI is less neurotoxic and can typically be continued. 6