Thursday, March 2, 2017

Antihistamines for Analgesia: Down to the Bone (Pain)

Clinicians in emergency departments across the country have increasingly become more savvy in their approach to the management of common pain conditions that patients may present with in this setting. In the effort to overcome the effects and consequences of the opioid abuse epidemic, great emphasis is now being placed in leveraging opioid-free alternatives in new ways for the management of these frequently encountered common pain conditions. This may involve utilizing target-specific agents in the mitigation of pain based on the known or hypothesized mechanism of pathophysiology, down to the very level of the receptor.

There is one niche patient population where managing pain may present somewhat of a challenge to the clinician - the cancer patient with bone pain following the administration of granulocyte-colony stimulating factors (G-CSFs), which are commonly used in conjunction with chemotherapy for the prevention of febrile neutropenia. G-CSFs have a notorious adverse effect of inducing bone pain, which can occur in upwards of 60% of patients who receive these agents (1-2).

The multimodal mechanism for induction of bone pain by G-CSFs has been theorized to involve increased sensitivity to peripheral nociception; propagation of the inflammatory pathway, with modulation and release of inflammatory cytokines; and remodeling and metabolism of the bone through activation of osteoblasts and osteoclasts and expansion of the cells of the bone marrow, which may result in an increased release of histamine (3).


Treatment options for G-CSF-induced bone pain have traditionally involved the use of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and opioid analgesics (3). These agents are not without their risks and any benefit that may be provided by these agents may be suboptimal, as they may not necessarily target the area of focus that drives the propagation of pain associated with this condition in the first place.

In the case of G-CSF-induced bone pain, one means of providing analgesia may very well mean utilizing H1-receptor antagonists (antihistamines). As early as the mid-1990s (4), H1-receptor antagonists have been evaluated for its utility as analgesics for the management of bone pain secondary to the administration of G-CSFs. Relatively recently, within this class of agents, loratadine has emerged as a treatment option for treatment of G-CSF-induced bone pain. Because it is a second-generation antihistamine, it is less likely to induce less sedation and other anticholinergic adverse effects relative to the first-generation antihistamines due to its reduced ability to cross the blood-brain barrier, which makes it relatively tolerable for most patients. In addition, as it was one of the first agents within this subclass to exist as a generic medication that is widely available over-the-counter, it has gained traction with this off-label use for treating G-CSF-induced bone pain (although that is not to say that other second-generation antihistamines are any more or less effective than loratadine in managing this condition).

There have been a number of case reports (5-6) published related to the successful use of loratadine in the treatment of G-CSF-induced bone pain, one which notably documented its use as abortive therapy for treating this condition in the emergency department (6). The results of a recently published pilot study consisting of 213 patients who randomized to receive a one-week regimen of either loratadine or placebo as a prophylactic agent in the treatment of bone pain following the use of G-CSFs demonstrated no significant differences in pain scores in patients with severe bone pain nor any significant improvement in quality of life for those patients with risk factors for developing bone pain (7). However, a number of factors may have contributed to these observed results, such as the use of other adjunct analgesic agents, the mixed patient population with multiple types of cancer, and the investigators' reliance on questionnaires distributed to patients as a means to assess pain status over the course of the study.

In contrast, the results of one open-label investigation (not surprisingly) demonstrate that loratadine is better tolerated than naproxen in managing pain associated this condition in those patients with a history of stages I through III breast cancer (8). In addition, one investigation is currently ongoing in recruiting participants to evaluate the effects of loratadine in mitigation of bone pain associated with administration of G-CSF in those patients with hematologic malignancies (9). Investigators of a rather unique but small observational, retrospective study of cancer patients evaluated the utility of using both H1 and H2-receptor antagonists (loratadine in combination with famotidine) as prophylactic agents for G-CSF-induced bone pain, and improvement in pain scores was noted (10). 

As important as it is to recognize the cause of pain associated with this phenomenon, it may be worth considering the use of loratadine as a treatment option for bone pain associated with G-CSFs. The typical adult daily dose of loratadine is 10 mg, which may be prescribed in the emergency department. With coordination from the oncologist, recommendations may be made for future use of loratadine in managing G-CSF-induced bone pain should the patient require subsequent administration of G-CSF.

Done and done.

References:
  1. Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin 2007; 23:2283-95.
  2. Gregory SA, Schwartzberg LS, Mo M, et al. Evaluation of reported bone pain in cancer patients receiving chemotherapy in pegfilgrastim clinical trials: a restrospective analysis. Community Oncol 2010; 7:297-308.
  3. Lambertini M, Del Mastro L, Bellodi A, et al. The five "Ws" for bone pain due to the administration of granulocyte-colony stimulating factors (G-CSFs). Crit Rev Oncol Hematol  2014; 89:112-28. 
  4. Gudi R, Krishnamurthy M, Pachter BR. Astemizole in the treatment of granulocyte colony-stimulating factor-induced bone pain. Ann Intern Med 1995;123:236-7.
  5. Romeo C, Quan L, Copeland L. Severe pegfilgrastim-induced bone pain completely alleviated with loratadine: a case report. J Oncol Pharm Pract 2015; 21:301-4.
  6. Moore K, Haroz R. When Hydromorphone Is Not Working, Try Loratadine: An Emergency Department Case of Loratadine as Abortive Therapy for Severe Pegfilgrastim-Induced Bone Pain. J Emerg Med 2017; 52:e29-e31.
  7. Moukharskaya J, Abrams DM, Ashikaga T, et al. Randomized phase II study of loratadine for the prevention of bone pain caused by pegfilgrastim. Support Care Cancer 2016; 24:3085-93.
  8. Guinguindo A, Vanni L, Maxwell C, et al. The effect of prophylactic naproxen, prophylactic loratadine, or no prophylaxis on bone pain in patients with breast cancer receiving chemotherapy and pegfilgrastim. J Adv Pract Oncol 2017; 8 [Abstract].
  9. Evaluation of loratadine for G-CSF-induced bone pain in patients with hematologic malignancies. Available at: https://clinicaltrials.gov/ct2/show/NCT02305979 [Accessed 1 March 2017].
  10. Gavioli E, Abrams M. Prevention of granulocyte-colony stimulating factor (G-CSF) induced bone pain using double histamine blockade. Support Care Cancer 2017; 25:817-22.

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