Drug for Depression Mutes Chemo Nerve Pain

Nick Mulcahy

April 02, 2013

The antidepressant duloxetine (Cymbalta, Eli Lily) is an effective treatment for the peripheral nerve pain caused by neurotoxic chemotherapy, according to a study published in the April 3 issue of JAMA.

The authors report that 5 weeks of duloxetine produced a "clinically and statistically significant improvement in pain control," compared with placebo.

This 231-patient study is the first large phase 3 trial to demonstrate an effective intervention for the nerve pain caused by platinum and taxane agents (mainly paclitaxel and oxaliplatin), write the authors, led by Ellen Smith, PhD, from the University of Michigan School of Nursing in Ann Arbor.

The findings are "practice changing," Dr. Smith said when she presented them last year at the annual meeting of the American Society of Clinical Oncology.

The results are important but not surprising, according to Marie Bakitas, DNSc, from the University of Alabama at Birmingham School of Nursing, who was not involved in the study.

"Duloxetine is being used in clinic now, and it is clearly an efficacious drug," she told Medscape Medical News in an email. "This study is key because it provides the evidence needed to support practice."

The 5-week crossover trial was conducted by Cancer and Leukemia Group B and involved patients 25 years and older who were treated in community and academic settings. They were eligible to participate if their average weekly pain score, rated on a 10-point scale, was at least 4.

Patients were randomized to receive either duloxetine followed by placebo or placebo followed by duloxetine.

Over the study period, the decrease in average pain was greater in patients receiving once-daily oral duloxetine than in those receiving placebo (1.06 vs 0.34; =.003).

In patients receiving duloxetine, pain scores decreased "relatively quickly, within the first week of therapy," the authors write.

A majority of the patients treated with duloxetine first reported some decrease in pain, whereas a minority of patients treated with placebo first did (59% vs 38%).

Overall, 30% of duloxetine-treated patients reported no change in pain and 10% reported increased pain.

Already Approved for Diabetic Neuropathy

Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine, which are key neurotransmitters that suppress the transmission of painful peripheral stimuli, the authors explain. The drug is approved by the US Food and Drug Administration for pain related to diabetic neuropathy.

Approximately 20% to 40% of patients with cancer who receive neurotoxic chemotherapy will develop painful chemotherapy-induced peripheral neuropathy, the authors report. The condition can persist from months to years after the completion of chemotherapy.

Dr. Bakitas likens peripheral neuropathy to "background noise." She noted that "it is always there" and, although sometimes unnoticeable, can be exacerbated by stress or fatigue or other factors.

Most randomized controlled trials of a variety of drugs with diverse mechanisms of action have revealed "no effective treatment," according to the authors.

But Dr. Bakitas is a champion of other methods of treatment for neuropathy.

She uses gabapentin with or without low-dose methadone. Other "effective coanalgesics" include topicals (such as lidocaine), physical therapy, acupuncture, and massage. Nonpharmaceutical treatments "are often neglected but can be very useful," Dr. Bakitas said.

Might Be Best With Platinums

The study participants were treated with chemotherapy between April 2008 and March 2011. Study follow-up was completed in July 2012.

Initial treatment consisted of either duloxetine 30 mg daily for 1 week followed by duloxetine 60 mg daily for 4 weeks or placebo for 5 weeks.

Participants were stratified by chemotherapeutic drug and comorbid pain risk.

Duloxetine was "safe and well-tolerated," which is consistent with other studies, write the authors. The antidepressant was also associated with improved function and quality of life, both of which were secondary outcomes of the study.

Initially, only patients who had received paclitaxel or oxaliplatin could participate. Eligibility was later expanded to allow previous treatment with single-agent docetaxel, nanoparticle albumin-bound paclitaxel, or cisplatin.

The authors point out that exploratory analyses suggest that patients who receive platinums get more benefit from duloxetine than those who receive taxanes.

This study was supported by a grant from the NCI Division of Cancer Prevention and the Alliance Statistics and Data Center. Drug and placebo were supplied by Eli Lilly. The authors and Dr. Bakitas have disclosed no relevant financial relationships.

JAMA. 2013;309:1359-1367. Abstract

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