This article focuses on the response rate to short‐acting immediate‐release oral opioids for control of breakthrough pain in advanced cancer patients treated by palliative care physicians.
Keywords: Palliative care, Pain, Opioid, Breakthrough pain, Breakthrough cancer pain, Episodic pain, Rescue medication, Incidental pain, Cancer
Abstract
Background.
There is limited evidence about the response of breakthrough pain (BTP) to the most commonly used oral immediate‐release (IR) opioids. Our aim was to determine response rate to oral IR opioids for BTP control in patients with advanced cancer.
Materials and Methods.
In this prospective study, palliative care outpatients, with advanced cancer and adequately managed background pain, were asked to complete a self‐administered survey. We assessed patients’ baseline demographics, pain characteristics, alcoholism (CAGE questionnaire), tobacco and substance abuse, and Edmonton Symptom Assessment Scores (ESAS). We determined the effectiveness of oral IR BTP opioids by using a 7‐point Likert scale ranging from “very ineffective” to “very effective.” “Effective” and “very effective” were defined a priori as a good response to IR opioids for BTP.
Results.
Of 592 evaluable patients, 192 (32%) had background pain of ≤3 (ESAS pain scale 0–10). Among these 192 patients, 152 (79%) reported BTP, 143/152 (94%) took oral IR opioids for BTP, and 127/143 (89%) responded to a median dose of 10% of the total morphine equivalent daily dose. In univariate logistic regression analysis, younger age (odds ratio [OR], 0.94 per year; p = .008), higher ESAS scores for pain (OR, 1.32; p = .012), anxiety (OR, 1.24; p = .017), and dyspnea (OR, 1.31; p = .007) had statistically significant association with poor response to IR opioids for BTP. In multicovariate logistic regression, adjusted for age, a higher ESAS dyspnea score was significantly associated with poor response to oral IR opioids (OR, 1.44; p = .002).
Conclusion.
The vast majority of patients with advanced cancer with adequately controlled background pain reported a good response to oral IR opioids for BTP, supporting their use in clinical practice.
Implications for Practice.
Oral immediate‐release opioids are standard treatment for cancer breakthrough pain. However, information regarding treatment response to these commonly used opioids is limited. This study provides information that the vast majority of patients with advanced cancer, with adequately controlled background pain, reported good response to oral immediate release opioids for managing their breakthrough pain episodes. Results of this study support the use of conventional oral immediate release opioids that are relatively inexpensive and readily available for management of breakthrough pain in patients with advanced cancer.
Introduction
Breakthrough pain (BTP) has been defined as “a transient exacerbation of pain that occurs either spontaneously, or in relation to a specific predictable or unpredictable trigger, despite relatively stable and adequately controlled background pain” [1], [2]. The terminology was first introduced in 1989 as incidental pain in the Edmonton staging system for cancer pain and was defined as “pain aggravated suddenly as a result of movements, swallowing, defecation or urination” [3]. The frequency of BTP has been reported approximately 40% to 60% in patients with cancer in various studies [4], [5]. Clinical characteristics of BTP are highly variable, but it is typically described as having rapid onset, short duration (30–60 minutes), and high severity [6], [7], [8], [9], [10]. Patients with uncontrolled BTP are also reported to have more functional impairment, worse mood, and more anxiety [7], [11] than patients with better controlled BTP.
Opioids are the mainstay of cancer pain management [12], [13], [14], [15]. The main pharmacological treatment for BTP is a rescue medication with a short‐acting immediate‐release (IR) oral opioid at a 10% to 15% dose of the total daily dose of regular around‐the‐clock opioids [12], [13], [14], [15], [16]. Because of their reliable safety profile and cost‐effectiveness, oral IR opioids are still the most commonly used BTP medications in the outpatient setting. In recent years there have been studies comparing different transmucosal fentanyl products with oral immediate release opioids (mainly morphine) for management of BTP in patients with cancer [17], [18], [19], [20]. In our experience, most patients report an adequate clinical response with immediate release oral opioids, but there is paucity of evidence on the response of BTP to commonly used oral opioids such as oral morphine, which has not been specifically tested for management of BTP in cancer population except as a comparator [18]. Without this empirical data, it is impossible to know how many patients would be eligible to receive alternative routes of BTP analgesics such as transmucosal fentanyl formulations, which are comparatively expensive and have limited geographic availability [12].
The purpose of our study was to determine the response rate to oral IR opioids for control of any type of breakthrough pain in patients with advanced cancer treated by palliative care physicians, for cancer pain management, at an outpatient supportive care center.
Materials and Methods
This prospective cross‐sectional survey study was approved by the institutional review board at the University of Texas MD Anderson Cancer Center. A total of 600 patients with advanced cancer, treated with regular around‐the‐clock opioids for background cancer pain at our outpatient supportive care center, were asked, during their routine follow‐up appointment, to complete a self‐administered 15‐ to 20‐minute survey. Prior screening was conducted through chart review by the research assistant. Advanced cancer was defined as locally advanced, metastatic, or locally recurrent disease for a solid tumor or primary progressive or relapsed/refractory disease for a hematologic malignancy. All patients were able to understand, read, write, and speak English. Patients with delirium or acute symptom distress were excluded. Written consent was obtained from all patients prior to enrollment in this study.
Information was collected for patients’ baseline demographics, pain characteristics, alcoholism (CAGE questionnaire), tobacco use and substance abuse [21], [22], [23], [24]. The CAGE (Cut down, Annoyed, Guilty, Eye opener) questionnaire is a validated four‐item tool to screen for history of alcoholism. A score of ≥1 in women and ≥2 in men is considered positive with 85% sensitivity and 90% specificity to detect alcohol abuse and/or dependency [23], [24].
Symptom burden was assessed using the Edmonton Symptom Assessment System (ESAS), which is a validated tool for regular assessment of symptom distress in the palliative care setting. Patients are asked to grade severity of their symptoms from 0 (no symptom) to 10 (worst symptom) in the last 24 hours. ESAS has a high test‐retest reliability of >0.8 and has been validated in many clinical settings, including the cancer population [25], [26].
The survey consisted of questions regarding patient's experience of their background pain (defined as “the usual constant pain you may always experience if you do not take regular pain medications”) and episodes of breakthrough pain (defined as “brief episodes of intense pain, which could be a sudden worsening of your background pain, or it can be a pain different from your background pain”) during last week as well as the day before the follow‐up appointment. The effectiveness of BTP medication was assessed with the use of a 7‐point Likert scale ranging from “very ineffective” to “very effective”; the terms “effective” and “very effective” were defined a priori as a response to IR opioids for BTP. There was no follow‐up or repeat survey. Enrollment was conducted between June 2014 and September 2016.
Data were also collected for type and dose of opioids for background pain control (as extended‐release [ER] formulations), and for BTP. Doses of opioids taken were converted to a morphine equivalent daily dose (MEDD) using standard equianalgesic conversion ratios.
Statistical Analysis
We recruited 600 patients who visited the outpatient Supportive Care Center at MD Anderson Cancer Center to determine the proportion of patients who reported a good response (“very effective” or “effective”) to oral IR opioids for BTP. Patients who reported otherwise were grouped into the category of poor response. Responses were summarized in patients who reported adequately controlled background pain (ESAS pain score of ≤3) and had oral IR opioids for BTP, by the proportion of patients who reported a response (“effective” or “very effective”) to opioids for BTP and the associated 95% confidence interval.
Standard descriptive statistics such as mean, standard deviation, median, interquartile range, frequency, and percentage were provided for patients’ demographics, ESAS at enrollment, tobacco history, substance abuse history, and BTP questionnaire. The Wilcoxon rank sum test was used to determine differences in continuous variables of interest between good (“effective” or “very effective”) and poor (all the rest) responders to BTP medications. The chi‐squared test or Fisher's exact test, whichever was appropriate, was used to determine the associations between categorical variables and response (good vs. poor). Univariate logistic regression was used to determine the factors associated with poor response to BTP medications. Stepwise selection was used to determine the final model in the multivariate logistic regression. All tests were two‐sided, and a p value of ≤.05 was considered statistically significant. All computations were carried out in SAS version 9.3 (SAS Institute Inc., Cary, NC).
Results
Of 600 enrolled patients with advanced cancer, 592 (99%) were evaluable (8 patients had missing data), and 192 (32%) reported background pain of ≤3 (ESAS pain scale 0–10). Among these patients, 152 (152/192, 79%) reported having BTP, and 143 (143/152, 94%) took oral IR opioids for BTP; 127 (127/143, 89%) responded. Figure 1 summarizes the patient eligibility algorithm.
Figure 1.
Patient eligibility algorithm.
Table 1 shows the characteristics and demographics of patients who were evaluable, reporting background pain of ≤3, having BTP and taking oral IR opioids for BTP (n = 143).
Table 1. Demographic and clinical characteristics of eligible patients with background pain ≤3 who reported breakthrough pain and took oral immediate‐release opioids.
Total of 143 patients for all variables except substance abuse (n = 122), tobacco history (n = 139), and CAGE at enrollment (n = 129).
This p value indicates statistical significance.
Abbreviations: BTP, breakthrough pain; CAGE, Cut‐down, Annoyed, Guilty, Eye‐opener (questionnaire for alcoholism); ESAS, Edmonton System Assessment Scale; IQR, interquartile range; IR, immediate release; STD, standard deviation.
Patients with poor response to oral immediate release opioids were younger (p = .02). These patients also reported a statistically significant higher pain intensity (p = .01, measured by using ESAS‐pain on a scale of 0–10) upon enrollment.
Among patient taking breakthrough pain medications (n =143), a total of 107 patients (75%) had college or higher education, and 27 (19%) were employed full time. Patients with college or higher education responded more likely to oral IR opioids (p = .03). There was no statistical difference in the employment status between the responders and nonresponders.
The most commonly used ER formulations for background pain control were morphine‐ER (n = 57, 40%) and oxycodone‐ER (n = 32, 22%), whereas morphine (n = 53, 37%), hydromorphone (n = 36, 25%), and oxycodone (n = 28, 20%) were the most commonly used immediate release BTP opioids.
Doses of opioids taken were converted to an MEDD for analysis. Among responders, the median (interquartile range [IQR]) BTP‐MEDD (total opioid dose for BTP taken over 24 hour) was found to be 30 mg (IQR, 15–45 mg), whereas a “single” dose of oral IR opioid for BTP control was a median of 10% of total regular MEDD (Table 2).
Table 2. Total morphine equivalent daily dose, breakthrough pain morphine equivalent daily dose, and oral immediate release opioid single dose for breakthrough pain control as percentage of total morphine equivalent daily dose.
Abbreviations: BTP‐MEDD, breakthrough pain morphine equivalent daily dose; IQR, interquartile range; IR, immediate release; T‐MEDD, total morphine equivalent daily dose.
Majority of the patients reported “never” to nausea (102/143; 71%), confusion (103/143; 72%), or sweating (115/142; 81%) when taking the additional doses of opioids for breakthrough pain control. Sleepiness was reported as “sometimes” and “never” by 52/143 (36 %) and 45/143 (31%), respectively. There were no statistically significant differences among the responders and nonresponders in terms of these side effects.
Using univariate logistic regression, younger age (odds ratio [OR] 0.94 per year, p = .008) and higher ESAS scores for pain (OR, 1.32; p = .012), anxiety (OR, 1.24; p = .017), and dyspnea (OR, 1.31; p = .007) showed statistically significant association with poor response to oral IR opioids for BTP (Table 3). The multicovariate logistic regression, with stepwise selection for the final covariates included in the model, indicates that, adjusted for age, a higher ESAS dyspnea score was significantly associated with poor response to IR oral opioids (OR, 1.44; p = .002; Table 3).
Table 3. Factors associated with poor response to oral immediate‐release opioids for breakthrough pain.
This p value indicates statistical significance.
Abbreviations: CI, confidence interval; ESAS, Edmonton System Assessment scores at the time of enrollment; OR, odds ratio.
Discussion
Our results indicate that the vast majority (89%) of patients with advanced cancer with breakthrough pain who had adequately controlled background pain (rated as ≤3) found oral IR opioids to be either effective or very effective in controlling their BTP episodes (Fig. 1). In most cases, the opioids used for BTP control were the same as those used as ER formulations for management of chronic background cancer pain. In our practice, we limit the use of different opioids for controlling background pain along with BTP at the same time, because using different opioids limits the choices for opioid rotation later in case of opioid‐induced neurotoxicity [27], [28], [29], [30]. Our study found that the single dose of oral IR opioid for BTP control was a median of 10% of the total MEDD (Table 2), which confirms findings from previous studies and guidelines [13], [14].
Effective management of breakthrough (episodic) cancer pain remains an ongoing challenge for the palliative care community. The consensus and standard of care has been to use 5% to 15% (up to 20%) of the MEDD in the form of an oral immediate release opioid to manage such transient episodes of pain [13], [14], [15], [16]. Some reviews suggest individual titration based on patients’ response irrespective of association with around‐the‐clock extended release dose [1], [2], always ensuring that background pain is adequately controlled [12], [13], [14], [15], [31], [32]. There have been studies comparing different transmucosal fentanyl products with oral immediate release opioids (mainly morphine) for management of BTP in patients with cancer [17], [18], [19], [20]. Our experience with patients with advanced cancer has been of an adequate clinical response with immediate release oral opioids, but there is a paucity of evidence on the response of BTP to commonly used oral opioids such as oral morphine, which has not been specifically tested for management of BTP in cancer population except as a comparator [18]. Transmucosal agents have an important role in the management of breakthrough cancer pain when traditional analgesics have failed, but they also carry the risk of common side effects like somnolence, nausea and dizziness, and sufficient saliva is required for adequate administration and delivery of such sublingual and buccal preparations [12], [33]. Current evidence on majority of such transmucosal preparations comes from data obtained from pharmaceutical industry‐sponsored randomized controlled trials and needs to be reviewed in this context [15]. Our data show that patients reported low frequency of side effects while using IR oral opioids for BTP control. More research is needed to determine the best tolerated type and dose of BTP opioid.
Our data show that 400/592 (68%) of patients with advanced cancer reported high background pain control (>3). However, the majority of these patients were coming for their first or second follow‐up visit to the palliative care clinic. Dalal et al. have reported that the number of patients who were able to achieve their personal pain goal or a clinical response to pain after a first follow‐up is low [34]. This also emphasizes that majority of patients with advanced cancer have complex pain syndrome(s) and require several visits to achieve meaningful improvement in pain. There remains a need to continue efforts toward improvement of pain management in patients with advanced cancer.
To our knowledge, this is the first prospectively designed study aimed solely at determining the response rate to commonly used BTP oral IR opioid analgesics. The results of this study will be helpful in designing clinical trials aimed at improving BTP analgesia. These results also affirm that a subgroup of patients with advanced cancer (who are younger and have higher ESAS scores for pain, anxiety, and dyspnea) requires closer monitoring and may need a relatively higher dose of BTP analgesia compared with those who are older and have lower ESAS scores. Our finding of a higher ESAS dyspnea score (when adjusted for age) as a significant factor predicting poor response to oral IR opioids emphasizes the importance of a more global symptom assessment and not just pain using symptom assessment tools such as ESAS [25], [26], [35] in oncology clinics during routine follow‐up visits while patients are on active oncological treatment. Such patients who express higher degree of symptom distress can then be identified and referred earlier to a palliative care team [36], [37], [38], [39], [40].
A limitation of our study is that the data were collected from a single institution. Also, the analgesic doses were optimally titrated by palliative care specialists. Results may be different in other settings in which such management is provided by nonspecialists. Another limitation is using a questionnaire that can be considered subjective and hard to analyze adequately in a heterogeneous group of patients with advanced cancer. Our data also do not allow us to determine the relative efficacy of various IR opioids. Our findings show that 16 patients who exhibited poor response were younger, had a higher level of education, and had high symptom scores for pain and dyspnea at presentation. Multivariate analysis showed that very few factors are predictive of poor response to BTP opioids, and those included younger age and the presence of dyspnea. Such patients should undergo closer follow‐up and closer titration of BTP medications. Unfortunately, it is challenging to draw firm conclusions from subanalyses given the low number of nonresponders in our study (n = 16, 11%). Future research is necessary to better characterize these factors and should also aim to determine whether there are any significant differences in efficacy between IR opioids.
In the small proportion of patients who do not respond to initial measures, a multidimensional treatment plan should be attempted [41] with a personalized pain management approach that optimizes pain therapy by introducing other measures such as palliative radiation therapy [42], adjuvant agents for lancinating neuropathic pain [12], [13], [14], invasive procedures such as percutaneous cordotomy [43], [44], and/or rapid acting transmucosal preparations, if available [45], [46], [47].
Our data reassure us that the practice of using IR oral opioids for management of BTP is appropriate and results in good pain control in patients with advanced cancer.
Conclusion
The vast majority of patients with advanced cancer with BTP reported good response to oral IR opioids, supporting the use of these opioids in clinical practice.
Acknowledgments
The authors acknowledge the staff at the outpatient supportive care center, as well as our patients and their families. We also acknowledge the Department of Scientific Publications at The University of Texas MD Anderson Cancer Center for assistance with review and editing of this manuscript. This study was partially supported by Biostatistics Shared Resources at MD Anderson, NIH grant CA16672 (Minjeong Park & Diane D. Liu). This study was presented in part as a poster at the 15th World Congress of the European Association for Palliative Care (EAPC)‐Progressing Palliative Care, Madrid, Spain, May 18–20, 2017.
Contributed equally
Author Contributions
Conception/design: Ahsan Azhar, Yu Jung Kim, David Hui, Susan E. Frisbee‐Hume, Julio A. Allo, Eduardo Bruera
Collection and/or assembly of data: Ahsan Azhar, Vishidha R. Balankari, Margeaux Chiou Epner, Janet Williams, Susan E. Frisbee‐Hume, Julio A. Allo, Eduardo Bruera
Data analysis and interpretation: Ahsan Azhar, Ali Haider, David Hui, Minjeong Park, Diane D. Liu, Julio A. Allo, Eduardo Bruera
Manuscript writing: Ahsan Azhar, Yu Jung Kim, Ali Haider, David Hui, Vishidha R. Balankari, Margeaux Chiou Epner, Minjeong Park, Diane D. Liu, Eduardo Bruera
Final approval of manuscript: Ahsan Azhar, Yu Jung Kim, Ali Haider, David Hui, Vishidha R. Balankari, Margeaux Chiou Epner, Minjeong Park, Diane D. Liu, Eduardo Bruera
Disclosures
The authors indicated no financial relationships.
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