Abstract
Background
Neutropenia is a common complication of cancer and cancer treatments. Granulocyte colony-stimulating factors (G-CSF) are medications that stimulate the bone marrow to produce neutrophils, which are critical to treat and/or prevent febrile neutropenia, a potentially deadly complication of cancer. There are two FDA-approved forms of G-CSF: filgrastim (Neupogen) and pegylated-filgrastim (Neulasta). Filgrastim is typically administered intravenously or subcutaneously daily for 10–14 days; pegfilgrastim is administered subcutaneously in a single dose once per chemotherapy cycle. The most prevalent and consistent side effect of G-CSF is bone pain. This Fast Fact will describe the symptoms, prevalence, potential etiology, and treatment of G-CSF-induced bone pain.
Clinical Presentation
Pain typically begins 1–3 days after the first dose of a G-CSF, peaks at 3–5 days, and resolves by day 7–8. The bone pain often is described as a deep ache, which can be intermittent or constant and vary from mild to severe. Most often it is located where there is high bone marrow activity: the pelvis, lower back, sternum, ribs, and the long bones of the femur or humerus. It is typically highest after the first cycle of G-CSF and decreases or stabilizes after subsequent cycles.
Risk Factors
Patients younger than 55 are more likely to experience G-CSF-induced bone pain, but sex or type of cancer (e.g., solid tumor versus hematological) do not appear to be risk factors. 1 Filgrastrim and pegylated filgrastim have similar incidences of bone pain (65%) and severe bone pain (7%).2,3 Taxanes (which are part of many chemotherapy regimens for breast, lung, prostate, gastric, and esophageal cancer) are associated with a similar syndrome—diffuse aching discomfort, most often in legs, hips, and lower back that evolves over 1–7 days—and it may not be possible to distinguish between them. 4
Causes
While the pathophysiology of G-CSF-induced bone pain is not fully understood, bone marrow expansion is considered the most likely cause. G-CSF causes rapid proliferation of myeloid progenitor cell colonies, increasing intraosseous pressure that stretches the periosteum and activates nearby nociceptive pain receptors, an inflammatory cascade, and histamine levels.2,5
Treatment
Most research on the treatment of G-CSF-induced bone pain is on pharmacologic prevention.
Methods for this include:
Anticipatory guidance: Informing patients of the natural timeline and expected resolution of pain related to G-CSF can relieve stress and help patients cope with the pain. G-CSF dose reduction: If a patient experiences a pattern of debilitating G-CSF-induced bone pain, a dose reduction in subsequent cycles may be considered. Inform the treating oncology team and pharmacist if you suspect GSF-induced bone pain in a patient so they can consider this option. NSAIDs: Naproxen 500 mg twice daily for 5–8 days has been shown to be effective in reducing overall incidence, duration, and severity in G-CSF bone pain when initiated the morning before pegfilgrastrim in a phase 3 randomized controlled trial.
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Notably, many patients receiving G-CSF stimulators have contraindications to NSAIDs—for example, thrombocytopenia, renal impairment, and heart failure. So, while NSAIDs may be the most evidence-based pharmacotherapy for this type of pain, it is often not a practical choice for many patients. Acetaminophen: Based on its safety profile, acetaminophen is commonly used for G-CSF-induced bone pain in patients with solid tumors. However, patients who have a primary or secondary bone marrow disease (e.g. leukemias and lymphomas) are often already neutropenic or will become neutropenic. Thus, these patients are often counseled to avoid acetaminophen so that early warning signs of sepsis are not masked by acetaminophen.
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Antihistamines—Case reports have described striking resolution of refractory pain from G-CSF induced bone pain with antihistamines such as loratadine 10 mg daily.5,8 Dual antihistamine blockade with both loratadine 10 mg and famotidine 20 mg when initiated 30 minutes before G-CSF has been associated with low cost, low risk, and significant reduction in pain scores.
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Opioids—In situations where patients have severe, refractory G-CSF-induced pain and/or contraindications to the above therapies, it may be reasonable to prescribe short courses of opioids. Corticosteroids—While corticosteroids are routinely used in the treatment of bone pain in patients with cancer, there is no direct evidence suggesting their efficacy in G-CSF bone pain.
Expert Opinion
All patients receiving G-CSF medications should be provided with anticipatory guidance about potential bone pain. Prophylactic prescription of an analgesic prior to the first dose of a G-CSF medication is recommended. 10 However, expert opinion falls short of providing specific guidance on a particular analgesic. For patients with hematological malignancies and severe neutropenia, NSAIDs and acetaminophen are often relatively contraindicated. Therefore, a one-week prophylactic administration of loratadine 10 mg and famotidine 20 mg daily, starting on the day of the first G-CSF dose, is a reasonable regimen. If this dual antihistamine regimen has not been effective enough in past rounds of G-CSF, then in opioid-naive patients, a trial of low-dose, short-acting, as-needed opioid may be reasonable.