Kirshner, J.J., Heckler, C.E., Janelsins, M.C., Dakhil, S.R., Hopkins, J.O., Coles, C., & Morrow, G.R. (2012). Prevention of pegfilgrastim-induced bone pain: A phase III double-blind placebo-controlled randomized clinical trial of the University of Rochester Cancer Center Clinical Community Oncology Program Research Base. Journal of Clinical Oncology, 30, 1974–1979.

To determine whether naproxen could prevent or decrease the incidence and/or severity of pegfilgrastim-induced bone pain

A baseline assessment questionnaire was administered prior to treatment asking the presence, location, and duration of bone or joint pain, as well as how the pain was treated. A second set of questions asking whether there was development of new bone or joint pain, location, onset, duration, and severity of the effect of the assigned medication was given to patients at the time of pegfilgrastim administration. Any additional analgesia taken by the patient was also recorded. Questionnaires were completed at home and mailed. Patients were telephoned at home as a reminder to mail in their questionnaires. Enrolled patients received 500 mg of naproxen PO or placebo instructed to take prior to pegfilgrastim and continue BID. Patients were then asked to record pain severity on a 0–10 scale and duration in a daily diary. Serious adverse events (SAEs) were reported to local investigators at the University of Rochester Cancer Center Community Clinical Oncology Program research base. Other symptoms were recorded but not reportable (e.g., sleep disturbance, pain other than bone pain, fatigue).

• The study reported on 510 patients.
• The sample was 86% female and 14% male.
• Patients had a diagnosis of nonmyeloid cancer, including breast (67%), lung (10%), gynecologic (6%), hematologic (7%), and other cancers (7%).
• Patients were 18 years of age or older and were able to understand English. 
• Patients were excluded from the study if they were pregnant or nursing or had active gastrointestinal (GI) bleeding, history of GI bleeding, history of gastric or duodenal ulcers, heart surgery in the past six months, allergy to nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin, and a creatinine level more than 1.5 times the upper limit of normal. They could not be taking NSAIDs or therapeutic dose of aspirin or warfarin.

• Mutlisite (multicenter trial)
• Setting not specified

• Patients were undergoing active treatment.
• The study has clinical applicability for elderly care; late effects and survivorship; and end-of-life and palliative care.

The study was a phase III, double-blind, placebo-controlled, randomized trial.

• Pain questionnaire
• Standard symptom inventory
• National Cancer Institute’s Common Terminology Criteria for Adverse Events
• Daily diary rating pain (0–10 scale), severity, and duration

African Americans experienced more bone pain than white patients. The naproxen group showed improvement in pain reduction versus placebo. Area under the curve for pain was 7.71 for the placebo group and 6.04 for the naproxen group (p = 0.037). Naproxen decreased maximum pain from 3.40 to 2.50 (p = 0.005), incidence from 71.3% to 61.1% (p = 0.020), duration from 2.40 to 1.92 (p = 0.009), and severe pain from 27% to 19.2% (p = 0.048). Bone pain reached maximum at day 3, where naproxen patients experienced the most benefit. Patients receiving naproxen took less prescription and nonprescription pain medication. Six SAEs occurred in the naproxen group, and six SEAs occurred in the placebo group, with all SAEs unlikely or determined to be unrelated to the intervention.

There is a high incidence of pain in patients receiving pegfilgrastim. Naproxen seems to decrease incidence, duration, and severity.

The pain questionnaire was not presented in the article, and further studies may not reproduce similar results. Patients were called at home to complete the survey; prescription and nonprescription medications that were taken in addition to the naproxen and timing of the survey may have impacted results. It is also possible that the individual responding to the call may not have been the study participant. The study does not address whether individuals with other existing pain conditions were in the study or excluded or whether there were other pain conditions present at the start of the study that may have impacted results.

This study indicates there a is a difference in pain experience with different races, which may impact practice in terms of treating pain and the patient population being treated. Additional research and education are needed to investigate this difference. These results may be helpful in treating some patients’ pain; however, more work is needed to find treatments for those who cannot seek this treatment or who derive limited or no benefit from it. More than 60% of patients in this study still experienced pain, with approximately 20% experiencing severe pain. It seems this study has a good start to recognizing the existence of pegfilgrastim-induced pain and has tested a somewhat helpful intervention. However, there is still a need for more studies with different approaches to pain control and factors to predict incidence, severity, and ability to prevent pegfilgrastim-induced bone pain. The benefit of using naproxen is that it is low cost and has very few SAEs, which will need to be considered in future studies.