Oral Loratadine in the Management of G-CSF-Induced Bone Pain: A Pilot Study

Design

Prospective, non-experimental, single-center study

N= 12

Objective

To ascertain if bone pain induced by granulocyte-colony stimulating factors (G-CSFs) can be alleviated or eliminated by oral antihistamine loratadine

Study Groups

All patients (N= 12)

Inclusion Criteria

Patients undergoing chemotherapy for a diagnosis of breast, colorectal, or genitourinary cancer and receiving G-CSF as part of their regimen

Exclusion Criteria

Taking daily antihistamines but not for bone pain; taking daily non-steroidal anti-inflammatory drugs, except aspirin, for long-term conditions; receiving bone-modifying agents for bone pain associated with metastatic disease of other long-term conditions; contraindications to loratadine

Methods

Pain was assessed using the Brief Pain Inventory (BPI), and was self-administered by each patient. The BPI was initially completed before the first chemotherapy cycle and again on day 7 after the first cycle. Subsequent BPI assessments were conducted on the first day of each chemotherapy cycle. Pain severity was measured on a scale of 0 to 10, with higher scores indicating greater pain severity. Patients also identified the primary pain sites over different chemotherapy cycles.

Oral loratadine (10 mg) was administered starting on day 1 of cycle 2 if the patient's pain score was ≥ 3 and was continued for the study duration. The BPI was recorded at each subsequent chemotherapy cycle to monitor pain levels.

Duration

Outcome Measures

Primary: Reduction or elimination of bone pain

Secondary: Determination of the association between patients' vitamin D and magnesium levels and pain 

Baseline Characteristics

All patients (N= 12)

Age, years

Female

BMI, kg/m2

Non-smoking status

12 (100%)

Cancer diagnosis

Breast

Genitourinary

Colorectal

7 (58%)

4 (33%)

1 (8%)

Chemo cycles completed

Cycle 1

Cycle 2

Cycle 3

Cycle 4

Cycle 5

0 

1 (8%)

2 (17%)

6 (50%)

3 (25%)

48.45 ± 25.39

Vitamin D supplement

3 (25%)

Magnesium levels, mmol/L

0.773 ± 0.883

Magnesium supplement

0

BMI, body mass index

Results

Pain Medication and treatment at each chemotherapy cycle

Post-cycle 1

None

Loratadine 10 mg

Loratadine and Ibuprofen as needed

Loratadine and Tramadol as needed

Ibuprofen as needed

Tramadol as needed

The study identified that the most commonly reported pain area across all chemotherapy cycles was lower front and back pain on both sides (n= 15; 48.8%), followed by the front and back right upper body (n= 4; 12.9%). All participants began oral loratadine in cycle 2, with some also taking ibuprofen (n= 1) or tramadol (n= 2). The use of additional pain medication decreased after loratadine initiation, except for one participant who continued tramadol as needed. Daily pain initially increased before decreasing post-cycle 1, with mean average pain diminishing over time. There was a significant negative correlation between initial pain levels and vitamin D levels (r= –0.677; p= 0.045), though this should be interpreted cautiously due to the small sample size. No significant correlation was found between magnesium levels and pain before cycle 1, but significant negative correlations were observed in cycles 2 (r= –0.642; p= 0.024) and 4 (r= –0.822; p= 0.012).

Adverse Events

Study Author Conclusions

InpharmD Researcher Critique

Although the results of this study indicate that oral loratadine is a safe and effective option for managing G-CSF-induced bone pain, the small sample size limits the ability to draw definitive conclusions. Furthermore, not all patients could return on day 7 after the first chemotherapy course for their BPI assessment. Consequently, the researchers had to rely on patient recall, which could potentially affect the accuracy of the results. Additional research is needed to confirm these findings.

Randomized Phase II Study of Loratadine for the Prevention of Bone Pain Caused by Pegfilgrastim

Design

Multicenter, randomized, double-blind, placebo-controlled, phase 2 trial

N= 227

Objective

To evaluate whether loratadine would decrease the incidence of pegfilgrastim-induced significant back or leg bone pain (SP) in a high-risk population

Study Groups

Loratadine (n= 22)

Placebo (n= 24)

Inclusion Criteria

Age 18 years or older; Eastern Cooperative Oncology Group performance status of 0 to 3; adequate renal function and hepatic function; histologically or cytologically documented malignancy; scheduled to receive pegfilgrastim with two consecutive cycles of the same chemotherapy with at least a 14-day interval between cycles

Exclusion Criteria

History of hypersensitivity or intolerance to antihistamines; concurrent use of antihistamines during or for 2 days prior to the study period except for a single dose of antihistamine as required for administration of chemotherapy or blood transfusion; concomitant use of amiodarone; history of prior use of pegfilgrastim or granulocyte colony-stimulating factor (G-CSF)

Methods

The study included an observation (OBS) stage followed by a treatment stage (TRT). Patients receiving an initial dose of pegfilgrastim 6 mg after chemotherapy were enrolled into the OBS. Those who developed SP were eligible to enter the TRT and were randomized (1:1) to receive loratadine 10 mg or matched placebo daily for 7 days starting on the day of pegfilgrastim administration. Analgesic use at baseline was permitted, but patients were instructed not to use analgesics prophylactically in the absence of pain or for other indications.

Duration

February 2011 to December 2013

Outcome Measures

Baseline Characteristics

Loratadine (n= 22)*

Placebo (n= 24)*

Age, years

Male

Primary site

Breast

Lung

Other gastrointestinal

Other malignancies

Colorectal

54.6%

13.6%

13.6%

13.6%

4.6%

66.7%

4.2%

8.3%

16.7%

8.3%

Taxane administration

NSAID use

Day 1

Day 8

18.2%

45.5%

8.3%

16.7%

Non-NSAID use

Day 1

Day 8

22.7%

40.9%

25%

33.3%

*Of the 65 patients who developed SP during the OBS phase, 46 were randomized in the TRT, with 1 patient not receiving allocated treatment and 1 being lost to follow-up.

Results

Endpoint

Loratadine (n= 22)

Placebo (n= 24)

p-value

Analgesic benefit from loratadine prophylaxis

Taxane therapy was associated with an increase in WPS scores after pegfilgrastim regardless of whether a patient received loratadine (1.73 increased to 5, p<0.001) or placebo (1.7 increased to 6, p= 0.007)

No significant difference in day 1 Functional Assessment of Cancer Therapy – Bone Pain (FACT-BP) scores was observed between study arms (p= 0.330). Additionally, there was no significant change in mean FACT-BP scores between the time before and after pegfilgrastim use within each arm.

Adverse Events

Not disclosed

Study Author Conclusions

This study demonstrated that prophylactic administration of the antihistamine loratadine at standard dose does not decrease the incidence of significant pegfilgrastim-induced bone pain or improve quality of life in patients at higher risk of developing pain, but subsequent elevation of the neutrophil count following pegfilgrastim is correlated with higher incidence of severe bone pain.

InpharmD Researcher Critique

NOLAN: A randomized, phase 2 study to estimate the effect of prophylactic naproxen or loratadine vs no prophylactic treatment on bone pain in patients with early-stage breast cancer receiving chemotherapy and pegfilgrastim

Design

Multicenter, open-label, randomized, 3-arm phase II study

N= 600

Objective

To evaluate the effects of prophylactic naproxen, prophylactic loratadine, or no prophylactic treatment on bone pain in patients with breast cancer receiving chemotherapy and pegfilgrastim.

Study Groups

No prophylaxis (n= 198)

Naproxen (n= 200)

Loratadine (n= 202)

Inclusion Criteria

Adult female patients with newly diagnosed, untreated breast cancer (stage I-III); Eastern Cooperative Oncology Group (ECOG) performance status ≤2; will utilize pegfilgrastim once per cycle for 4 cycles of adjuvant or neoadjuvant chemotherapy.

Exclusion Criteria

Previously received chemotherapy weekly; ongoing chronic pain condition; prior use of chemotherapy or previous granulocyte colony-stimulating factor (G-CSF; filgrastim, pegfilgrastim, or other); chronically using oral steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or oral antihistamines; history of gastrointestinal (GI) bleeding or ulcers

Methods

Patients were stratified by age (either <65 or ≥65) and chemotherapy type (taxane or non-taxane) and then randomized 1:1:1 within each stratum between either no prophylaxis, oral loratadine 10 mg daily, or oral naproxen 500 mg twice daily. Medications were administered for 5 days in each cycle starting on the same day the patient received pegfilgrastim. Patients could receive chemotherapy for ≥4 cycles, but only the first 4 cycles were utilized for trial data.  

Bone pain was assessed by a pain severity scale of 0 through 10 utilizing two methods. One method was physician questioning patients regarding any adverse event (AE) since their last clinic visit on day 1 of cycles 2, 3, and 4 and during the safety follow-up visit occurring between days 30 to 37 since the last dose of study medication. AE severity was graded using Common Terminology Criteria for Adverse Events, version 3.0. A second method was a patient survey completed daily for 5 days, starting on the day the patient received pegfilgrastim.

Patients were asked to record detailed information regarding medication use for alleviating bone pain in a log and to give to their healthcare provider at the next clinic visit; any additional treatment or medication outside of prophylactic study medications was provided as supportive care to patients at the discretion of the provider. 

Duration

Enrollment: November 2012 to March 2015

Intervention: 5 days for each chemotherapy cycle following pegfilgrastim dose

Follow-up: 30 to 37 days following study drug discontinuation

Outcome Measures

Primary: All-grade bone pain during the first cycle

Secondary: All-grade bone pain and severe (grade 3 or 4) bone pain during cycles 2 through 4 and pain across all cycles (cycles 1-4); patient-reported bone pain and maximum patient-reported bone pain by cycle and across all cycles

Baseline Characteristics

No prophylaxis (n= 191)

Naproxen (n= 196)

Loratadine (n= 200)

Age, years

54.8 ± 10.7

53.2 ± 11.7

54.6 ± 10.9

Race

White

Black or African American

Asian

Other

148 (77.5%)

33 (17.3%)

3 (1.6%)

7 (3.7%)

166 (84.7%)

27 (13.8%)

3 (1.5%)

0 

173 (86.5%)

2 (11.5%)

1 (0.5%)

3 (1.5%)

Calculated BSA, m²

1.899 ± 0.235

1.875 ± 0.240

1.881 ± 0.217

Disease stage

I

II

III

58 (30.4%)

94 (49.2%)

39 (20.4%)

41 (20.9%)

96 (49%)

59 (30.1%)

51 (25.5%)

104 (52%)

45 (22.5%)

Chemotherapy regimen^†

Stratified to and received taxane

Stratified to taxane, received non-taxane

Stratified to and received non-taxane

Stratified to non-taxane, received taxane

88 (46.1%)

19 (9.9%)

83 (43.5%)

1 (0.5%)

94 (48%)

17 (8.7%)

84 (42.9%)

1 (0.5%)

92 (46%)

21 (10.5%)

85 (42.5%)

2 (1%)

Abbreviations: BSA, body surface area

† Stratification factor used in randomization

A total of 391 patients (97.3%) received at least 1 dose of naproxen or loratadine: 193 received naproxen and 198 received loratadine.

One patient stratified to <65 was actually ≥65 years of age.

Results

All-grade bone pain

No prophylaxis (n= 191)

Naproxen (n= 196)

Loratadine (n= 200)

Cycle 1

89/191 (46.6%)

79/196 (40.3%)

85/200 (42.5%)

-6.3; -16.7 to 4.1

-4.1; -14.5 to 6.3

2.2; -8 to 12.4

Cycle 2

61/178 (34.3%)

62/180 (34.4%)

67/193 (34.7%)

0.2; -10.2 to 10.6

0.4; -9.8 to 10.7

0.3; -9.9 to 10.5

Cycle 3

56/165 (33.9%)

60/176 (34.1%)

68/188 (36.2%)

0.2; -10.5 to 10.8

2.2; -8.3 to 12.8 

2.1; -8.3 to 12.4 

Cycle 4

66/162 (40.7%) 

68/169 (40.2%)

68/188 (38%)

-0.5; -11.7 to 10.7

-2.8; -13.7 to 8.2 

-2.2; -13.1 to 8.6

Across all cycles

121/191 (63.4%)

116/196 (59.2%)

122/200 (61%)

-4.2; -14.4 to 6

-2.4; -12.5 to 7.8

1.8; -8.3 to 12

Abbreviations: AE, adverse event; CI, confidence interval

The full analysis set includes all patients who received primary prophylaxis with pegfilgrastim.

Maximum patient-reported bone pain (i.e., maximum value of each patient’s bone pain values across survey days 1-5 within each cycle) had reported significant differences in treatment benefits for naproxen in cycle 4 (p= 0.032), as well as for loratadine in cycle 1 (p= 0.006), cycle 4 (p= 0.032), and across all cycles (p= 0.041).

When analyzing treatment benefits based on age stratification, a treatment benefit for naproxen was observed in cycle 1 (p= 0.015) and cycle 4 (p= 0.032), while a treatment benefit for loratadine was observed in cycle 1 (p= 0.002), cycle 4 (p= 0.020), and across all cycles (p= 0.015); no treatment benefit was seen for any prophylaxis method in patients ≥65 years.

When analyzing treatment benefits based on regimen stratification, a treatment benefit for loratadine was observed in cycle 1 (p= 0.040) for taxane-based chemotherapy, as well as cycle 1 (p= 0.039), cycle 2 (p= 0.019), cycle 4 (p= 0.021), and across all cycles (p= 0.035) in the nontaxane-based chemotherapy.

Naproxen (n= 193)

Loratadine (n= 198)

Patients reporting treatment-related AEs*

Worst grade of ≥ 2

Worst grade of ≥ 3

Worst grade of ≥ 4

Serious AEs

Life-threatening AEs

Fatal AEs

30 (15.5%)

11 (5.7%)

2 (1.0%)

0

1 (0.5%)

0

0

7 (3.5%)

3 (1.5%)

0

0

0

0

0

Patients reporting treatment-related AEs (≥ 1% of patients in any group)

GI disorders

Nausea

Abdominal pain

Constipation

Dyspepsia

Diarrhea

GERD

Vomiting

General disorders

Fatigue

Nervous system disorders

Headache

Skin and SubQ tissue disorders

Blood and lymph system disorders

Musculoskeletal and CT disorders

21 (10.9%)

5 (2.6%)

3 (1.6%)

3 (1.6%)

3 (1.6%)

2 (1.0%)

2 (1.0%)

2 (1.0%)

5 (2.6%)

3 (1.6%)

3 (1.6%)

3 (1.6%)

3 (1.6%)

2 (1.0%)

2 (1.0%)

1 (0.5%)

1 (0.5%)

0

1 (0.5%)

0

1 (0.5%)

0

0

5 (2.5%)

4 (2.0%)

2 (1.0%)

1 (0.5%)

1 (0.5%)

0

1 (0.5%)

Abbreviations: CT, connective tissue; GI, Gastrointestinal; GERD, gastroesophageal reflux disease; SubQ, subcutaneous

* Treatment-related AEs are AEs associated with naproxen and loratadine (not chemotherapy or pegfilgrastim)

Analysis of bone pain from AE reporting in subgroups based on stratification factors at randomization (age <65 vs. ≥65 years, taxane vs. non-taxane chemotherapy) did not show meaningful differences between treatment groups in number of patients who reported bone pain.

Adverse Events

Common and Serious Adverse Events: See Results

Percentage discontinued due to Adverse Events: overall (4.7% in naproxen group vs. 0 in loratadine group); due to gastrointestinal symptoms (3.6% vs. 0) or abdominal pain (1.6% vs. 0)

Study Author Conclusions

Given its tolerability, its ease of administration, and the consistent reductions in patient-reported bone pain observed in this study, treatment with 5 days of once daily loratadine in each chemotherapy cycle should be considered for patients receiving chemotherapy and pegfilgrastim.

InpharmD Researcher Critique

Due to the study design not including hypothesis testing and no statistical adjustment being made for multiple comparisons, the p-values should be considered nominal. Additionally, the open-labeled nature and the ability for patients to self-treat pain mean that findings should be interpreted with caution.

Effect of Loratadine for Pegfilgrastim-Induced Bone Pain

Design

Observational, cross-sectional, single-center study

N= 66

Objective

To address the gaps in literature and to explore the use of and perceived effectiveness of loratadine versus acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) in women with breast cancer treated with pegfilgrastim

Study Groups

All patients (N= 66)

Inclusion Criteria

Women >18 years old treated with either hormone or chemotherapy for breast cancer who completed the breast cancer survey

Exclusion Criteria

Confused or cognitively impaired, receiving their first treatment

Methods

A survey of complementary and alternative therapy (SCAT) was used with an additional twenty-five specific individual stand-alone items to address the aims of the study. These items included demographic data, basic oncology health history (chemotherapy, hormonal therapy, radiation therapy), and OTC medication use (NSAIDs, acetaminophen, loratadine), as well as items related to bone pain and its management. Additionally, the survey included questions about bone pain, its management, and who recommended specific pain medications for preventing or managing pegfilgrastim-induced bone pain.

Duration

February 2016 to February 2020

Outcome Measures

Efficacy of loratadine compared to NSAIDs and acetaminophen for pegfilgrastim-induced bone pain in breast cancer patients on a 0 to 10 scale

Baseline Characteristics

All patients (N= 66)

Age range, years

Menopausal Status

Pre-menopausal

Post-menopausal

21 (34%)

41 (66%)

Treatment

Chemotherapy

Chemotherapy + Hormone

47 (73%)

8 (13%)

Results

Medication

All patients (N= 66)

NSAID

Efficacy range*

15 (35%)

3 to 9

Acetaminophen

Efficacy range*

34 (68%) 

6 to 10

Loratadine

Efficacy range*

40 (89%)

5 to 10

Abbreviations: NSAID= Nonsteroidal Anti-Inflammatory Drug 

* Range is based on a scale of 0-10 for how effective the medication is with 0 being the least and 10 as the most.

Fewer than half of the patients (n= 30; 45%) reported experiencing pain, while more than half (n= 45; 69%) were using acetaminophen, NSAIDs, or loratadine, either alone or in combination, to prevent it. Among these, ten participants used both NSAIDs and loratadine.

Adverse Events

Not disclosed

Study Author Conclusions

Acetaminophen, loratadine, and NSAIDs are inexpensive and easily available. Acetaminophen has some hepatic toxicity side effects, and NSAIDs are often contraindicated due to thrombocytopenia, gastrointestinal side effects, and renal dysfunction. In contrast, loratadine is well tolerated with minimal adverse effects and has the potential to prevent pegfilgrastim-induced bone pain.

InpharmD Researcher Critique

This study is limited by its small sample size and it was conducted within a single healthcare setting, which restricts the generalizability of the results. Consequently, the study design cannot assess cause-and-effect relationships. Furthermore, the patient population lacks diversity, with a predominance of Caucasian individuals, which may impact the generalizability of the findings to a more diverse population. Additionally, it is unknown if medications prevented pain in the patients who were pain-free.

When Hydromorphone Is Not Working, Try Loratadine: An Emergency Department Case of Loratadine as Abortive Therapy for Severe Pegfilgrastim-Induced Bone Pain

Design

Case presentation

A 49-year-old female with a medical history of breast cancer, hypertension, diabetes mellitus, and obesity presented to the emergency department (ED) with severe generalized pain. She had undergone her first chemotherapy session, which included doxorubicin and cyclophosphamide, seven days before her ED visit, and had received a pegfilgrastim injection six days before arrival.

The patient reported pain intensity of 10/10, with aching pain localized to her bilateral knees, pelvis, lumbar spine, sternum, and bilateral shoulders. She appeared in significant distress, crying due to the pain. Initial evaluation indicated that her pain was an adverse effect of the pegfilgrastim injection.

The patient had taken therapeutic doses of acetaminophen and ibuprofen orally two hours before arriving at the ED, without any relief. In the ED, she was administered intravenous hydromorphone, initially 1 mg followed by an additional 2 mg, but experienced minimal pain relief. After consultation with the on-call oncologist, she was given 10 mg of oral loratadine.

Following this treatment, she reported a significant reduction in pain, with her pain score decreasing from 10/10 to 5/10. The patient was observed to be more comfortable, lying flat and relaxed in the hospital bed. She was discharged with a follow-up appointment with her oncologist scheduled for the following week. According to the available medical records, she has not returned to the ED for pain management since then.

Study Author Conclusions