Ellen M. Lavoie Smith, PhD
The antidepressant duloxetine (Cymbalta) relieved pain associated with chemotherapy-induced peripheral neuropathy for 59% of patients in a phase III study, making it the first drug to prove effective for treating the common adverse event, according to research presented at the American Society of Clinical Oncology (ASCO) annual meeting.
The findings are expected to change clinical practice, as the drug potentially offers a new way to achieve quality-of-life improvements for a large pool of patients. Peripheral neuropathy affects 20% to 30% of patients treated with taxanes and platinum-based chemotherapy, with a spectrum of severity that can affect such daily activities as walking, working, sleep patterns, and mood. Although many patients may experience manageable numbness and tingling in the hands and feet, others find peripheral neuropathy chronic and debilitating.
“This study is significant because to date there has been no study that has demonstrated that any drug works for painful chemotherapy-induced peripheral neuropathy,” lead investigator Ellen M. Lavoie Smith, PhD, assistant professor in the School of Nursing at the University of Michigan, Ann Arbor, said in an interview. She released the results at a press briefing Sunday.
Smith said researchers sought to focus on the role of the central nervous system in peripheral neuropathy, rather than on the nerve damage that can result from chemotherapy.
“This is really a very paradigm-shifting way of thinking about this,” said Smith. “It’s changing our thinking to focus more on what is happening in the brain that could be facilitating and maintaining pain.”
She said duloxetine works by increasing the amount of serotonin and norepinephrine, which are pain-inhibiting neurotransmitters in the brain, and patients may experience relief because the drug is working in the central nervous system to inhibit the ascent of painful stimuli from the peripheral system to the brain.
The clinical study was a double-blinded, placebo-controlled crossover design involving 231 patients primarily with gastrointestinal or breast cancers who had previously reported high levels of pain from peripheral neuropathy due to taxane or platinum treatment. The patients were randomized to receive duloxetine followed by placebo versus placebo followed by duloxetine.
Participants took a 30-mg duloxetine capsule daily for 1 week, followed by 2 capsules daily (60 mg) for 4 additional weeks. The Brief Pain Inventory-Short Form (BPI-SF) was used at baseline and then weekly. The primary endpoint was the change in the BPI-SF scores within the initial treatment period. Of the 231 participants, 185 (80%) completed the initial treatment period.
Those patients who received duloxetine during the initial treatment period had a larger average decrease in pain score than those receiving placebo (59% vs 38%, respectively). Of those patients, 33% in the duloxetine-first group as opposed to 17% in the placebo group experienced a decrease in pain ≥30%, the threshold considered clinically significant.
Patients in the duloxetine-first group also were less likely to report no change in pain compared with the placebo group (30% vs 34%, respectively) and less likely to report an increase in pain (11% vs 28%, respectively).
Smith said the most frequently reported adverse events were fatigue, insomnia, nausea, somnolence, and dizziness. Most of the events were moderate, with severe effects reported by 7% of patients (7 patients). Overall, 11% of patients (12 patients) dropped out of the study because of side effects.
The gradual dosing of duloxetine helped limit side effects, said Smith. She added investigators looked at patterns in 3 studies of the drug in other clinical settings and determined that one factor in the higher adverse event level in those trials may have been the dosing pattern.
Several oncologists at the press briefing said they welcome a new tool to help patients.
Nicholas J. Vogelzang, MD, who moderated the press briefing, said numbing, tingling, and pain are fairly common among patients with cancer. Vogelzang is a medical oncologist at the Comprehensive Cancer Centers of Nevada, and serves as chair and medical director of the Developmental Therapeutics Committee for US Oncology Research.
“The work here shows that we have made a step forward,” he said. “It’s obviously not going to work for every patient, but the majority of patients get pain control. Although their nerves may still be somewhat imperfect or damaged, we begin to see some glimmer for these patients.”
Cymbalta, which the US Food and Drug Administration initially approved in 2004, is indicated for the treatment of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Eli Lilly and Company markets the drug.