Question: Why is there increasing interest in the use of antihistamines for G-CSF–induced bone pain?
Answer: Febrile neutropenia (FN) can occur after chemotherapy treatment with a variety of regimens. The risk of developing FN is based on multiple factors, including the type of chemotherapy and a history of FN. The American Society of Clinical Oncology and the Infectious Disease Society of America state that prophylaxis for FN should be given when the risk for FN is greater than or equal to 20%.¹˒²
Prophylaxis for FN should include granulocyte colony stimulating factor (G-CSF), given 24 hours following each chemotherapy cycle.² Available G-CSF formulations include filgrastim (Neupogen) and tbo-filgrastim (Granix), which are given in daily injections for up to 14 days, and the long-acting pegfilgrastim (Neulasta), which is given in a single injection.³˒⁴
Bone Pain Etiology
G-CSF is effective at prophylactically decreasing the neutrophil nadir; however, it is not without side effects. Bone pain is a common side effect after both filgrastim and pegfilgrastim injection. The precise underlying mechanism behind the bone pain is unknown; it may be caused by expansion of bone marrow resulting from increases in hematopoietic progenitor cells and histamines as part of an immunologic response brought on by G-CSF.⁵ Histamine release has been implicated in bone marrow edema and pain.⁶ In addition, CSF receptors have been found on nerve fibers that may affect JAK-STAT, MAPK, and PI3K pathways that may be directly or indirectly implicated in pain modulation.⁵ Nevertheless, there remains uncertainty regarding the precise mechanism of bone pain.
According to the package inserts, bone pain associated with filgrastim and pegfilgrastim occurs in 24% and 31% of patients, respectively.³˒⁴ However, some believe that the actual clinical incidence of bone pain may be higher than has been reported.⁶˒⁷ A retrospective analysis published in Community Oncology Journal evaluated the incidence of bone pain associated with filgrastim and pegfilgrastim in multiple trials. This study compared the incidence of any bone pain and grade 3 or 4 pain. The incidence of bone pain in those receiving pegfilgrastim (62%) was slightly less than that in those receiving filgrastim (66%), which indicates that bone pain is very common among those receiving either G-CSF treatment.⁸However, grade 3 or 4 bone pain was more rare, accounting for less than 8% of all cases.⁸ Further analysis done in this study showed that bone pain was more common in patients <65 years old receiving taxane-based chemotherapy.⁷˒⁸ The incidence of G-CSF-induced bone pain also was more common after the first chemotherapy cycle and subsided with subsequent cycles.⁸
Treatment Options
Pain management options for G-CSF-induced bone pain include acetaminophen (Tylenol, others), nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.⁵˒⁷ Each of these options are appropriate treatments for cancer-related bone pain, according to the National Comprehensive Cancer Network (NCCN) guidelines.⁹ However, some patients do not obtain pain relief from NSAIDs and opiates. In those cases, physicians have prescribed antihistamines due to the proposed mechanism of action. There is limited reported use of antihistamines to treat G-CSF–induced bone pain; however, 2 drugs have shown promise in published literature.
A case report detailed the successful use of the second-generation antihistamine loratadine (Claritin) to treat G-CSF–induced bone pain that was resistant to NSAIDs.⁷ That report described a 67-year-old white female with a history of stage IV ovarian cancer who had been treated with neoadjuvant carboplatin plus paclitaxel, then debulking surgery, then adjuvant therapy with 5 more cycles of carboplatin plus paclitaxel. During the adjuvant chemotherapy phase, the patient developed neutropenia and required pegfilgrastim. She experienced severe pain (rated as 10 out of 10) that radiated down her legs and into her feet, which lasted approximately 10 days. Paclitaxel was not suspected to be the cause of the pain because the patient was previously treated with paclitaxel without a problem.
The patient had taken naproxen (400 mg tid) as first-line therapy and achieved no reduction in pain symptoms. She was then prescribed oxycodone (OxyContin, Roxicodone, others) (5-10 mg every 4-6 hours, as needed), which gave her minimal relief, and then hydromorphone (1-2 mg every 4-6 hours, as needed), which resulted in excessive sedation and confusion. Finally, she was prescribed loratadine (10 mg), which she was instructed to take the day before, the day of, and for 5 days after chemotherapy. With this therapy, she experienced no leg pain or myalgia. Loratadine use continued throughout the remainder of her treatment, which included a change in chemotherapy due to disease progression, without incidence of bone pain.⁷
These reports suggest the possibility that there may be another option for the prevention of G-CSF–induced bone pain. Loratadine, in particular, is inexpensive, is dosed once daily, and is a well-tolerated over-the-counter antihistamine. It is non-drowsy and considered safe in many patient populations. Its efficacy in preventing bone pain will require further investigation; however, these studies show there is potentially some benefit in patients who have not responded to NSAIDs.
Future Trials
10 The Phase II NOLAN trial, comparing naproxen and loratadine to reduce the incidence of bone pain in patients with breast cancer receiving pegfilgrastim, is scheduled to conclude November 2015.¹¹ Lastly, a trial investigating loratadine use in the prevention of pegfilgrastim-induced bone pain is scheduled to be completed in August 2018.¹²
The results of these trials should provide stronger clinical evidence of whether loratadine is effective in the prevention of G-CSF–induced bone pain.