Abstract
Background:
Seventy percentage of patients who receive paclitaxel have diffuse, refractory myalgias, and arthralgias. Based on anecdotal reports, this study explored whether loratadine, an antihistamine, palliates these symptoms.
Methods:
The medical records of postoperative ovarian and patients with endometrial cancer were studied, as these patients are routinely prescribed paclitaxel. Records were screened for patients who received paclitaxel and loratadine concurrently.
Results:
Forty patients are the focus of this report. Eight had paclitaxel-induced myalgias and arthralgias and then took loratadine; of these, 6 (75%; 95% confidence interval: 35%, 97%) manifested evidence of symptom improvement: “She did experience some migrating generalized body aches and pains…but this has resolved.” Of those already receiving loratadine but with no myalgias and arthralgias, only 11 of 32, or 34% (95% confidence interval: 19%, 53%), developed myalgias and arthralgias (in contrast to the previously reported symptom rate of 70%). No adverse events were clearly attributed to loratadine.
Conclusion:
These preliminary data support further study of loratadine for paclitaxel-induced myalgias and arthralgias.
Introduction
Paclitaxel is one of the most commonly prescribed antineoplastic agents. 1 -7 This chemotherapy agent causes a syndrome characterized by diffuse myalgias and arthralgias, both of which are resistant to opioids and other pain medications. 8 Patients report pain that typically begins 2 to 7 days after the initiation of paclitaxel, peaks on days 3 to 4, and remains consistent in intensity and duration with ongoing drug administration. 8 Although the dose and rate of infusion of paclitaxel impact the incidence and severity of these myalgias and arthralgias, 70% of patients who receive this chemotherapy agent have this syndrome. 8 Furthermore, some patients report pain that, at times, leads to cessation of chemotherapy, an observation that underscores the importance of investigating how best to palliative this syndrome. 9,10
The clinical consequences of paclitaxel-induced pain have prompted studies to investigate palliative options. Candidate interventions have included minocycline, auranofin, pregabalin, gabapentin, glutamine, glutathione, shakuyaku-kanzo-to, amifostine, and prednisone. 11 -20 However, all these interventions have resulted in clearly negative results or, at best, modest anecdotal reports of palliation.
Interestingly, the use of the antihistamine, loratadine, has received ongoing attention as a potential palliative intervention. As early as 2011, patients with cancer have used social media to attest to how loratadine helps to palliate their paclitaxel-induced myalgias and arthralgias. 21 Of parallel importance, a small report from Martoni and others describe how 5 of 9 patients acquired relief from paclitaxel-induced symptoms with an antihistamine; 3 reported complete relief of symptoms. 22 To our knowledge, few other studies have examined antihistamines and—specifically loratadine—for the palliation of paclitaxel-induced myalgias and arthralgias.
Hence, the goal of the current study was to further explore whether the antihistamine loratadine palliates paclitaxel-induced myalgias and arthralgias. We sought to assess whether patients who had taken loratadine appeared to acquire symptom relief and also whether patients who had been already taking loratadine for another indication appeared to develop these paclitaxel-induced symptoms at a lower rate than historically reported.
Methods
Overview
The institutional review board (IRB) of Mayo Clinic approved the current study, which was exploratory, descriptive, and hypothesis-generating in nature and which was undertaken to gather further data on the purported role of loratadine for the palliation of paclitaxel-induced myalgias and arthralgias. In view of the study design, the IRB allowed for a waiver of informed consent.
Ascertainment and Organization of Patient Data
We decided to focus on postoperative patients with either ovarian or endometrial cancer, as these patients are highly likely to receive postoperative paclitaxel on a consistent basis. To this end, the Mayo Clinic Tumor Registry provided a list of all such patients seen at the Mayo Clinic in Rochester, Minnesota between January 1, 2001, and December 31, 2017.
Patients were excluded if they received neither paclitaxel nor loratadine, if they had received inadequate doses of either drug (eg, paclitaxel was permanently stopped after a few drops because of an infusion reaction), if they had not received these agents within the same time interval, or if medical record content seemed sparse to the point of compromising our ability to assess the documentation of myalgias and arthralgias. Medical records were reviewed in depth for evidence of loratadine usage regardless of whether patients started taking it on their own or as per the recommendation of a health-care provider for any indication, although it was impossible to make such distinctions from the medical record.
We sought 2 categories of patients, based on diffuse myalgias and arthralgias, as defined by a concordant description of such symptomatology in the medical record. First, we screened medical records for patients who received postoperative paclitaxel, developed paclitaxel-induced myalgias and arthralgias, and then received loratadine. In this first category, we sought a clearly delineated temporal relationship between the use of loratadine and the potential for symptom improvement. Of note, in the first category, we recorded relevant quotations indicative of palliation or lack thereof with loratadine. Second, patients who were already taking loratadine with paclitaxel were also included, and we assessed whether or not they had developed symptoms. The medical records of all patients were reviewed in detail for evidence of paclitaxel-induced myalgias and arthralgias as well as for relevant demographic information.
Data Analyses
Data are presented descriptively with medians, ranges, and percentages; 95% confidence intervals are reported, as appropriate.
Results
Overview
A total of 862 medical records of patients administered paclitaxel were reviewed to ascertain the 2 patient categories described above (Figure 1). The first category consisted of 8 patients who had experienced paclitaxel-induced myalgias and arthralgias and took loratadine. The second consisted of 32 patients who were already taking loratadine but prior to the development of paclitaxel-induced arthralgias and myalgias.
Consort diagram.
Demographics
Demographics for all patients appear in Table 1. The median age within the cohort as a whole was 61 years (range: 41-79). Twenty-seven (67%) patients had ovarian cancer and the rest endometrial cancer.
Demographics.a
an = 40.
bNumbers in parentheses denote percentages of the entire cohort unless otherwise specified.
Palliation and Other Outcomes
In the first category of patients, 6 (75%; 95% confidence interval: 35%, 97%) of 8 patients who had developed paclitaxel-induced myalgias and arthralgia seemed to have had improvement in symptoms after loratadine (Table 2).
Medical Record Comments After Loratadine.a
an = 8.
These 6 patients with improved symptoms used a variety of other pain medications, including acetaminophen (6 patients), opioids (2 patients), and nonsteroidal anti-inflammatory agents (2 patients) with no clear symptom improvement from these other interventions. Notably, 1 patient with no symptom improvement with loratadine used all 3 of these classes of drugs and the other patient used opioids and acetaminophen.
In the second category of patients, or those already receiving loratadine, 21 of 32, or 66% (95% confidence interval: 47%, 81%), remained symptom-free. In other words, only 11 of 32 patients, or 34% (95% confidence interval: 19%, 53%), developed myalgias and arthralgias. Of note, no major adverse events that could be clearly attributed to the loratadine were observed.
Paclitaxel Cessation
Paclitaxel was never stopped because of myalgias and arthralgias. However, 1 patient needed to skip doses because of these symptoms, and, in 2 patients, the reason for stopping paclitaxel was difficult to assess.
Discussion
This study explored whether loratadine palliates or potentially prevents paclitaxel-induced myalgias and arthralgias in women with endometrial or ovarian cancer. Although our sample size that assessed symptom palliation is small (n = 8), we observed that as many as 75% of these patients appeared to report an improvement in symptoms with loratadine. Within the context of a larger group of patients who were assessed for symptom prevention (n = 32), we observed that only 34% of patients already taking loratadine developed paclitaxel-induced myalgias and arthralgias; this low rate contrasts with the 70% rate of symptoms cited in previous studies. 8 In effect, loratadine appears to change the course of this syndrome from one that affects the majority of patients to one that affects only a minority. Thus, we conclude that loratadine merits further study for paclitaxel-induced myalgias and arthralgias, particularly in view of the acceptable adverse event profile of this second-generation antihistamine.
Importantly, from a translational standpoint, the favorable observations reported in this study appear plausible. A relationship between antihistamines and paclitaxel-induced pain has been previously recognized. 23 -26 Gao and others described how mast cell stabilization leads to amelioration of paclitaxel-induced neuropathic pain, a situation that might be akin to paclitaxel-induced myalgias and arthralgias and thereby provides a mechanistic basis for the findings observed in the clinical data presented here. 26
Nonetheless, it should be noted that our study has limitations. First, an absence of symptoms in the medical record does not always indicate an absence of symptoms in the clinic. Furthermore, it was difficult to ascertain accurately all the reasons for holding paclitaxel, whether such cessation was related to myalgias and arthralgias or other issues, and whether loratadine was prescribed specifically for symptom control. Not all symptoms and the circumstances surrounding them are always noted in the medical record. For this reason, a prospective trial with meticulous monitoring of outcomes is important to demonstrate definitively the purported benefits of loratadine. 27 Second, one cannot overestimate the so-called “placebo effect” and the fact that our findings do not establish cause and effect with loratadine. In other words, when health-care providers or other patients suggest an intervention to patients, it is likely that a subgroup will report benefit independently of the efficacy of the intervention. In previous symptom control studies, a placebo effect—or report of symptom improvement—occurs in as many as 30% to 40% of patients prescribed an inert substance. 28,29 The above limitations speak to the importance of conducting a prospective clinical trial with loratadine in the future.
In conclusion, the results reported here suggest that loratadine benefits patients who have paclitaxel-induced myalgias and arthralgias. Our findings should be viewed with cautious enthusiasm in the absence of a prospectively conducted clinical trial and should serve to provide preliminary data in support of such a future trial.
Footnotes
Authors’ Note
The authors have full control of all primary data and agree to allow the journal to review the data if requested.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
