Smith, E.M., Pang, H., Cirrincione, C., Fleishman, S., Paskett, E.D., Ahles, T., . . . Alliance for Clinical Trials in Oncology. (2013). Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: A randomized clinical trial. JAMA: The Journal of the American Medical Association, 309, 1359-1367.

Determine the effect of duloxetine on pain severity

Patients were randomized to two study groups: group A subjects received 60 mg of duloxetine initially and then were crossed over to receive placebo and group B subjects initially received placebo and then were crossed over to duloxetine. The initial study period was five weeks. This was followed by a two-week washout period and then a final study period of an additional five weeks. Patients were assessed weekly. Use of other drugs that affect serotonin levels was not allowed. Concomitant use of other analgesics was allowed.

• N = 141
• MEAN AGE = 59 years (SD = 10.5 years)
• MALES = 37%, FEMALES = 63%
• KEY DISEASE CHARACTERISTICS: The majority of patients had gastrointestinal or breast cancer. All had received neurotoxic chemotherapy with taxanes or platinum compounds. 44% were considered high risk for peripheral neuropathic pain due to other conditions such as diabetes. All had at least grade 1 sensory pain on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v 3.0) and reported at least level 4 neuropathic pain on a 10-point scale for three or more months after completing chemotherapy.
• OTHER KEY SAMPLE CHARACTERISTICS: 81% were Caucasian; 14% were black.

• SITE: Multi-site 
• SETTING TYPE: Outpatient 
• LOCATION: United States

PHASE OF CARE: Transition phase after active treatment

Double-blind, placebo-controlled, crossover, randomized controlled trial

• Breif Pain Inventory (Short Form): Average pain severity was used as outcome.
• Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx)
• National Cancer Institute Common Terminology Criteria for Adverse Events (v 3.0)

Among patients who received duloxetine first, 59% reported some decrease in pain, 30% reported no change in pain, and 10% reported increased pain. Compared with placebo, there was a significant chance of receiving a 30% reduction in pain score (RR = 1.96, 95% CI 1.15-3.35) and a 50% reduction in average pain (RR = 2.43, 95% CI 1.11-5.30) with duloxetine. Analysis suggested a greater benefit in patients receiving platinums compared to those who received taxanes. Patients who received duloxetine in the second study period appeared to show greater reduction in average pain scores. Overall duloxetine treatment effect on pain was significant (p < .001). After initial treatment, 41% on duloxetine reported decrease in numbness and tingling in the feet versus 23% on placebo (p ≤ .05). This trend continued through the crossover period. In the duloxetine group, 11% dropped out due to adverse events, compared to 1% receiving placebo. More patients on duloxetine experienced nausea. Other adverse effects were similar between treatments. The most common adverse effects were fatigue and insomnia.

Compared to placebo, duloxetine treatment had a significant effect on pain from chemotherapy-induced peripheral neuropathy. Duloxetine also had some positive effect on numbness and tingling symptoms in the feet but not in upper extremities.

• Measurement validity/reliability was questionable.
• Subject withdrawals were ≥ 10%.
• Concomitant analgesics and changes in analgesics were not described.
• It is unclear why an apparent greater effect on average pain with duloxetine occurred in the second study period for group B. 
• There was an overall 19% drop-out rate.
• A higher proportion of grade 3 toxicities occurred with duloxetine.
• Only average pain, and pain interference during the initial study period, were compared, rather than comparison between the two study conditions. Why this was done is not clear..

Findings show that duloxetine can be effective in reducing pain from chemotherapy-induced peripheral neuropathy. Duloxetine also was associated with more adverse events. Nurses will need to monitor for adverse events, particularly for patients who may already be experiencing sleep wake disturbance and fatigue.