What is the best approach to treating a patient with multiple myeloma experiencing pain and burning in hands and feet due to bortezomib (subcutaneous Barsema), considering options like amitriptyline, duloxetine, hydrocodone, or pregabalin?

Treatment of Bortezomib-Induced Peripheral Neuropathy with Painful Burning

Pregabalin 150-600 mg/day is the best first-line treatment for this patient's bortezomib-induced painful burning neuropathy, combined with immediate dose reduction of bortezomib to 1.0 mg/m². 1

Immediate Bortezomib Dose Modification Required

This patient has Grade 1 neuropathy with pain (or Grade 2 if interfering with function), which mandates immediate action on the bortezomib dosing:

• Reduce bortezomib dose to 1.0 mg/m² immediately to prevent progression of neuropathy 1
• If already using IV administration, switch to subcutaneous route, which reduces peripheral neuropathy rates from 53% to 38% for all grades and from 16% to 6% for Grade 3-4 2, 1
• Consider weekly dosing instead of twice-weekly, which decreases Grade 3-4 peripheral neuropathy from 18% to 9% without compromising efficacy 1

The FDA label confirms that among patients with ≥Grade 2 peripheral neuropathy who had dose adjustments, 48% improved or resolved with a median of 3.8 months from first onset 3. Bortezomib-induced peripheral neuropathy is mostly reversible, unlike thalidomide-induced neuropathy which is often permanent 2.

First-Line Pharmacologic Treatment: Pregabalin

Start pregabalin at 150 mg/day (75 mg twice daily or 50 mg three times daily) as the primary symptomatic treatment 1, 4:

• Titrate to 300 mg/day (150 mg twice daily) if tolerated and pain persists 4
• Maximum dose is 600 mg/day (300 mg twice daily) if response remains inadequate 1, 4
• Continue for at least 3 months before declaring treatment failure 1, 4

The European Myeloma Network guidelines specifically identify pregabalin and duloxetine as effective for painful peripheral neuropathy, with calcium channel blockers like pregabalin and serotonin-norepinephrine reuptake inhibitors being "very effective, especially in painful PN" 2. Pregabalin is recommended as first-line by the American Society of Hematology 1.

Critical renal function assessment is mandatory before starting pregabalin, as dose adjustment is necessary in patients with reduced creatinine clearance 4. Calculate creatinine clearance using the Cockcroft-Gault equation 4.

Why Not the Other Options?

Duloxetine (Second-Line)

• Reserve duloxetine 30-60 mg/day as second-line treatment if pregabalin fails after 3 months at optimized doses or causes intolerable side effects 1, 4
• While duloxetine showed efficacy in preclinical models of bortezomib-induced neuropathy 5 and is effective for neuropathic pain 2, guidelines consistently place pregabalin first 1, 4
• Consider duloxetine earlier if the patient has comorbid depression, as it provides dual benefit 4

Amitriptyline (Not Recommended)

• Amitriptyline showed NO efficacy in preclinical models of bortezomib-induced peripheral neuropathy 6
• This is a critical distinction: while amitriptyline is effective for diabetic neuropathy 7 and general neuropathic pain 8, it specifically failed in bortezomib-induced neuropathy models 6
• The evidence directly contradicts using amitriptyline for this specific etiology of neuropathy

Hydrocodone (Third-Line at Best)

• Opioids are recommended only as second-line treatments in general neuropathic pain guidelines 8 or for breakthrough chronic pain while optimizing first-line therapy 4
• Tramadol (an opioid-like medication) showed efficacy in bortezomib-induced neuropathy models 6, but pure opioids like hydrocodone lack specific evidence for this condition
• The European Myeloma Network states opioids "can be effective" but should be "combined with other pain modulating drugs" 2, not used as monotherapy

Treatment Algorithm Summary

1. Immediately reduce bortezomib to 1.0 mg/m² and switch to subcutaneous if not already 1
2. Start pregabalin 150 mg/day, titrate to 300-600 mg/day over weeks 1, 4
3. Continue pregabalin for 3 months minimum before assessing efficacy 1, 4
4. If pregabalin fails or is not tolerated, switch to duloxetine 30-60 mg/day 1, 4
5. Add tramadol for breakthrough pain while optimizing first-line therapy 4
6. Monitor for improvement: median time to improvement is 47 days (range 1-529 days) after dose modification 3

Critical Pitfalls to Avoid

• Do not delay dose modification: 45% of patients who discontinued due to ≥Grade 2 neuropathy did so within the first three cycles 1
• Do not use high-dose vitamin C, as it may interfere with bortezomib metabolism and reduce efficacy 1
• Avoid high-dose pyridoxine (vitamin B6), especially in patients with renal insufficiency, as it can induce sensory neuron lesions 1
• Do not start pregabalin at high doses without gradual titration, as this increases intolerable adverse effects 4
• Never abruptly discontinue pregabalin or duloxetine; taper gradually to avoid withdrawal symptoms 4
• Do not declare treatment failure prematurely; pregabalin requires at least 3 months at optimized doses 1, 4

Monitoring Parameters

• Reassess at 2-4 weeks after reaching target pregabalin dose, then monthly 4
• Monitor for peripheral edema, weight gain, dizziness, and somnolence with pregabalin 4
• Grade neuropathy severity using Total Neuropathy Score if available 2, 4
• Expected improvement timeline: 73% of patients with Grade ≥2 neuropathy who discontinue or have Grade ≥3 neuropathy show improvement or resolution 1

Adjunctive Non-Pharmacologic Measures

• Wear loose-fitting shoes, roomy cotton socks, and padded slippers 1
• Keep hands uncovered at night 1
• Soak hands in icy water and massage for temporary pain relief 1
• Walk regularly to help circulation 1