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Intravenous Fentanyl for Dyspnea at the End of Life: Lessons for Future Research in Dyspnea

American Journal of Hospice & Palliative Medicine® 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1049909114559769 ajhpm.sagepub.com

G. S. Pang, MBChB, PhD1, L. M. Qu, MSN, RN1, Y. Y. Tan, MN, RN1, and A. C. P. Yee, MBBS, MRCP1

Abstract Objectives: To determine the efficacy of intravenous (IV) Fentanyl in dyspnoeic patients with advanced cancer. Methods: Dyspnoeic patients with advanced cancer satisfying the selection criteria received (IV) Fentanyl and were evaluated for response 24 hours post-administration in a prospective observational study. Results: Altogether 36 patients were enrolled into the study. However, data from only 16 patients could be analysed as 20 patients had died or were too sick to self-report scores. Seven out of 16 patients responded to IV Fentanyl although the result was not statistically significant (non-responders versus responders: 56.3% vs 43.8%, p ¼ 0.33). The strongest correlations for variables predictive of responder status were the absence of anxiety and lung metastases. Conclusions: This exploratory study shows that IV Fentanyl can alleviate dyspnea in some patients but is an example of the difficulties conducting dyspnea research. Future studies would benefit from novel developments in the areas of measuring dyspnea in dying patients and statistical analysis of small sample sizes. Keywords fentanyl, opioid, intravenous, dyspnea, cancer, lessons

Introduction Dyspnea is a highly distressing symptom occurring in 21% to 78% of patients with advanced cancer and increases as death approaches.1 Fentanyl is a highly lipophilic strong opioid, whose rapid onset of action and absence of active metabolites, makes it suitable for relieving acute dyspnea in the terminal phases of cancer. To date, there have been a total of 3 randomized doubleblind controlled trials (RCTs) and 11 reported observational studies (8 of 11 published in English-language journals)2,3 regarding the effect of fentanyl on relieving dyspnea. Three of the reported observational studies found benefit for the use of nebulized as well as oral transmucosal fentanyl (OTFC) in reducing dyspnea albeit in small patient numbers4-6 although results from RCTs have been inconclusive. However, study sizes, even in the RCTs, have been small ranging from 12 to 13 patients for each RCT3,7 and 1 to 35 patients for the observational studies. One RCT was even halted prematurely as only 2 patients over 18 months were recruited.8 None of the RCTs examined the use of intravenous (IV) fentanyl to relieve dyspnea in the terminal stages of life in patients with advanced cancer. In addition, fentanyl was administered via the nebulized, OTFC, or transdermal route in reported studies.2 There has been, so far, 1 case study in the literature reporting the use

of IV fentanyl in a single patient with nonsmall-cell lung carcinoma. Hence, we hypothesized that IV fentanyl could be efficacious for palliating acute dyspnea in hospitalized patients with terminal cancer. The IV route of administration was chosen as IV administration had the highest drug bioavailability and such patients often had an existing IV line enabling relatively painless drug administration for rapid relief. Furthermore, transdermal administration of fentanyl via a patch was unsuitable for relieving acute dyspnea and the OTFC or fentanyl ‘‘lollipop’’ was unavailable in Singapore. Given the previous reported difficulties in achieving large sample sizes for an RCT8 and the absence of a previous reported study testing our hypothesis of interest, we chose to undertake an exploratory observational study to evaluate the effect of starting an IV fentanyl infusion on dyspnea severity

1

Department of Palliative Medicine, National Cancer Centre Singapore, Singapore

Corresponding Author: G. S. Pang, Department of Palliative Medicine, National Cancer Centre, 11 Hospital Drive, Singapore, 169610 Singapore. Email: [email protected]

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2 (as measured by categorical scores) in hospitalized patients with terminal cancer.

Methods Institutional review board approval was obtained prior to commencing the study. Hospitalized patients with intact cognition under the care of the palliative medicine service at the National Cancer Centre, Singapore, with dyspnea deemed distressing by the patient or palliative medicine team and no contraindications to IV fentanyl administration, were eligible for the study. Patients who were receiving or had received thoracic radiotherapy in the month prior to study enrollment, a procedure performed 2 days prior to study enrollment to relieve dyspnea with patient-reported relief of dyspnea postprocedure and patients with contraindications to starting fentanyl therapy, were excluded. Intravenous fentanyl was administered as a continuous IV infusion over 24 hours to patients at a starting infusion dose deemed appropriate by the attending palliative care team. Patient-reported categorical scores for dyspnea severity were obtained at baseline (T0) and 24 hours after starting the infusion (T24), as our patient population was more adept with categorical rather than numerical scoring. Categorical scores were assessed as the patient-reported severity of dyspnea at the time of assessment. Responders to IV fentanyl were defined as patients who reported a reduction of at least 1 category in categorical score from baseline, at T24. Data collected on the predictor variables for response to IV fentanyl included age, gender, cancer type, presence of anxiety (as clinically determined by the research nurse), chronic heart, end-stage renal or respiratory disease, rib or pleural metastases, and concomitant respiratory complications such as pleural effusions, pneumonia, pulmonary edema. Information on hemodynamic and respiratory parameters, development of opioid adverse effects, and patientreported overall improvement in dyspnea severity from T0 to T24 was also collected. Predictor variables were recorded as present or absent except for age, hemoglobin, and physiological parameters, where the actual number was recorded. No pre-study sample size calculation was performed as this was an exploratory study.9 The one-proportion z test was used to ascertain for statistically significant differences in the proportions of responders versus nonresponders at T24. The Spearman rank correlation coefficient, r, was used to ascertain the relationship between predictor variables and response. The 2-tailed Fishers Exact test was used to infer statistically significant correlations between response and categorical variables, while the Mann-Whitney U test was used to ascertain for significant differences between median values in the 2 groups for continuous variables (SPSS statistics, IBM SPSS Statistics Version 18).

Results A total of 36 patients were enrolled for the study. However, data from 16 patients were eventually analyzed as 20 patients died before T24 or were too ill to self-report scores at T0 and/

or T24. With regard to the primary outcome of interest, no statistically significant difference (nonresponders versus responders ¼ 56.3% vs 43.8%, P ¼ .33) was observed between the proportion of nonresponders and responders to IV fentanyl at T24. The distribution of categorical scores for dyspnea at study entry was similar between the 2 groups with more than 80% of patients having dyspnea of at least moderate severity (Table 1). Two patients in the nonresponder group were on existing transdermal fentanyl, 1 patient on 37 mg/h and the other patient on 62 mg/h, while each of 3 patients in the responder group were on 25 mg/h of transdermal fentanyl at T0 (Table 1). None of the patients received morphine, intravenously or subcutaneously, from T0 to T24. Only 1 patient in the nonresponder group received 5 mg of oral quick-release morphine from T0 to T24. Of the 7 patients in the responder group, 3 received a blood transfusion in the 24 hours before T0 compared to 2 of 9 patients in the nonresponder group (Table 1). Starting infusion doses administered in this study ranged from 5 to 25 mg/h in the responder group and 5 to 35 mg/h in the nonresponder group. The median starting IV fentanyl infusion dose was 7.5 and 12 mg/h in the responder and nonresponder groups, respectively (Table 1). Although all 16 patients analyzed were alive at T24, 68.8% (n ¼ 11) of these patients died within the same hospital admission as study entry. The mean and median time from study entry to death in hospital for all analyzed patients who died was 7 and 5 days, respectively, confirming the role of dyspnea as a key symptom heralding imminent death.10 Not surprisingly, 7 of the 11 deaths occurred in the nonresponder group. Reduction in categorical dyspnea severity scores positively correlated (r ¼ .75) with patient-reported improvement in dyspnea severity at T24 and was statistically significant (P ¼ .009), suggesting that the effect of IV fentanyl could be perceived by patients. However, no statistically significant association or trend between response to fentanyl and changes in pulse, blood pressure, or respiratory rate was observed, demonstrating that objective commonly used clinical measures were not always reliable indicators of response. Median IV fentanyl doses consumed from T0 to T24 were higher in nonresponders compared to responders (227.5 vs 167.0 mg) although the difference was not statistically significant (P ¼ .43). The clinical characteristics of responders and nonresponders are shown in Table 1. The percentage of females was higher in the responder group compared to the nonresponders (71.4% vs 33.3%, respectively), and the mean age of responders was 5 years older than the nonresponders (66.6 vs 61.3 years, respectively). The strongest correlations observed in univariate analysis for variables predictive of responder status were negative correlations with presence of anxiety as determined clinically by the research nurse (r ¼ .52) and lung metastases (r ¼ .51) at study entry. The P value for these 2 correlations approached the .05 statistical threshold for significance (P ¼ .06 for anxiety and P ¼ .08 for presence of lung metastases at study entry). The effect size of the 2 variables on response was not estimated as effect sizes could be artificially inflated by small sample size. None of the responders were on

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Table 1. Characteristics of Responders and Nonresponders at Study Entry. Responders (n ¼ 7) Sociodemographics Mean age + sd in years Gender Race Primary cancer Lung Upper gastrointestinal Lower gastrointestinal Gynecological excluding breast Hematological Presence of metastases Lung Pleura Rib Treatment before study entry Receiving palliative chemotherapy Surgery in the past week prior to study entry Blood transfusion 24 hours prior to study entry Concomitant respiratory conditions at study entry Pneumonia Pulmonary edema Pleural effusion Mean hemoglobin (g/dL) + sd Comorbidities at study entry Chronic heart disease End-stage renal failure Chronic respiratory disease (non-COLD) Chronic obstructive lung disease (COLD) Anxious at study entry Opioids prior to study entry Transdermal fentanyl Morphine IV infusionb Subcutaneous Oral quick release Oral slow release Weak-moderate strength opioids, eg, tramadol Medications at study entry (T0) Diuretics Steroids Antibiotics Benzodiazepines Antipsychotics Categorical scores for dyspnea at study entry Mild Moderate Severe IV Fentanyl infusion dose started at T0 (mg/h) Mean + sd/median Mean + sd/median total IV fentanyl dose from T0 to T24 (mg) Physiological parametersc Median difference in pulse between T24 and T0 (beats/ minute) Median difference in BP between T24 and T0 (mm Hg) Median difference in respiratory rate (breaths/minute)

Nonresponders (n ¼ 9)

66.6 + 12.9 61.3 + 13.9 M ¼ 6 (66.7)b M ¼ 2 (28.5)a F ¼ 5 (71.4) F ¼ 3 (33.3) All patients analyzed were Chinese n n n n n

¼1 ¼3 ¼0 ¼2 ¼1

n¼2 n¼1 n¼3 n¼0 n¼3

Y ¼ 0 (0) Y ¼ 2 (28.6)

Y ¼ 4 (44.4) Y ¼ 2 (22.2) Nil for all patients

Y ¼ 0 (0)

Y ¼ 1 (11.1) Nil for all patients

Y ¼ 3 (42.9)

Y ¼ 2 (22.2)

Y ¼ 3 (42.9) Y ¼ 2 (28.6) Y ¼ 6 (85.7) 9.2 + 0.9

Y ¼ 3 (33.3) Y ¼ 4 (44.4) Y ¼ 4 (44.4) 9.4 + 1.7

Y ¼ 0 (0) Y ¼ 0 (0) Y ¼ 2 (28.6)

Y ¼ 2 (22.2) Y ¼ 2 (22.2) Y ¼ 0 (0) Nil for all patients

Y ¼ 1 (14.3)

Y ¼ 6 (85.7)

Y ¼ 2 (37 mg/h and 62 mg/h)

Y ¼ 3 (25 mg/h for each patient)

Y ¼ 1 (0.1 mg/h infusion)

Y ¼ 3 (infusion dose range ¼ 0.2-0.5 mg/h) 0 Y ¼ 4 (dosing range ¼ 2.5-5 mg/4h)

0 Y ¼ 5 (dosing range ¼ 2.5 mg/ 4 h-15 mg PRN) Y¼0 Y¼1

Y ¼ 1 (30 mg/12 h) Y¼1

Y ¼ 4 (57.1) Y ¼ 1 (14.3) Y ¼ 6 (85.7) Y ¼ 0 (0) Y ¼ 1 (14.3)

Y ¼ 6 (66.7) Y ¼ 0 (0) Y ¼ 9 (100) Y ¼ 2 (22.2) Y ¼ 1 (11.1)

1 (14.3) 4 (57.1) 2 (28.6)

1 (11.1) 5 (55.5) 3 (33.3)

10.0 + 7.6/7.5 217.7 + 174.1/167

14.3 + 11.3/12 276.1 + 201.3/227.5

4

2

9 4

3 2 (continued)

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4 Table 1. (continued)

Median time from study entry to death (days) Number of deaths occurring in the same hospital admission as study entry

Responders (n ¼ 7)

Nonresponders (n ¼ 9)

3.5 n ¼ 4 (57.1)

6 n ¼ 7 (77.8)

Abbreviations: sd, standard deviation; Y, variable is present; BP, blood pressure; IV, intravenous; mg, milligrams; mg, microgram; h ¼ hour; PRN, as and when required. a Numerals in parentheses and italics are the percentages of patients with that variable present. b IV morphine infusion stopped at study entry. c Physiological parameters are expressed as differences (value at T24 minus value at T0). A negative value for the difference ¼ value at T24 is lower than value at T0. A positive value for the difference ¼ value at T24 is higher than value at T0. T0 ¼ At study entry, T24 ¼ 24 hours after starting the continuous IV fentanyl infusion.

benzodiazepines at T0 or T24. Hence, the absence of anxiety in responders was not due to the use of anxiolytics such as benzodiazepines. No other statistically significant correlations were observed between response and other predictor variables in univariate analysis. Side effects were few with incidences of 6.3% for myoclonic jerks or pruritus (1 patient) and 12.5% for nausea and vomiting or nightmares (2 patients).

Discussion Our study is the largest prospective study to date examining the efficacy of IV fentanyl on acutely hospitalized patients with dyspnea having terminal cancer. Even so, we were only able to analysze data from the minority of patients (16 of 36 patients), as the rest had died by T24 or were too sick to self-report the severity of their dyspnea. However, the sample size in our study is comparable to those in previously reported RCTs and larger than most observational studies albeit different clinical study conditions within the same field of study. We observed that 7 of 16 patients responded to IV fentanyl, suggesting that IV fentanyl did benefit a subgroup of patients albeit not the overwhelming majority. This finding is in keeping with previous studies showing that opioids can alleviate dyspnea arising from different clinical conditions and settings including at the end of life.11-13 Notably, responder status in our study negatively correlated with the presence of anxiety as well as lung metastases at study entry with the following implications that opioid efficacy can be modulated by other factors such as disease-related anatomical alterations as well as emotional states. The ability of anxiety to modulate response to opioids hints at the likely involvement of multiple opioidergic and nonopioidergic pathways in the pathogenesis of dyspnea. Based on our findings as well as the literature, which supports the multifactorial nature of dyspnea,14 we may infer that opioids alone are unlikely to alleviate dyspnea of all types and severities to the same extent in every patient, which a previous randomized controlled trial of morphine to treat dyspnea has also shown.15 This has implications for the relevance of future studies evaluating the efficacy of monopharmacotherapy to treat dyspnea.

Although other predictors of opioid response have been reported including younger age ( 75 years), improved functional status, and the presence of significant heart disease,16 we had not observed these associations in our study due to small sample size, the low prevalence of advanced heart disease (22.2% in nonresponders only), and most patients were of Eastern Cooperative Oncology Group category 3 or 4 in our study. Reported predictors such as functional status are also not consistently predictive between studies.16,17 Interestingly, our study found that the absence of lung metastases correlated with responder status to IV fentanyl. Hypothetically, lung metastases may alter the mechanics of respiration such as normal elastic recoil of the lungs during expiration to increase intrathoracic pressure and facilitate expiratory airflow. In contrast, opioid drugs are thought to reduce respiratory inspiratory drive in the central nervous system.14 Hence, opioid-driven reduction in respiratory inspiratory drive, in the presence of dysfunctional respiratory mechanics, may be insufficient to significantly alleviate dyspnea with a large respiratory mechanical component. However, further in vivo studies would be required to verify this hypothesis. One of the key limitations in our study is the small number of patients, for which we could obtain comprehensive data for. The small sample size eventually analyzed in this study illustrates the common difficulty in obtaining a comprehensive data set based on patient-reported scores as well as high patient numbers for drug efficacy studies in dyspnea.8 Previously validated dyspnea scales recommended for use in palliative care such as the Modified Borg scale18 can be difficult to use in those with altered consciousness, cognition, clinically unstable, or are very weak, which are common events as death approaches.19,20 The lack of a reliable objective clinical measure, as observed from the lack of correlation between respiratory rate and response in our study, further compounds difficulties in assessing dying patients for improvements in dyspnea severity following drug administration. Structured assessments of emotion such as anxiety, which can influence dyspnea severity, would be preferable. However, the study patients could be very ill as they were hospitalized inpatients, where answering structured questionnaires could be burdensome and produce large amounts of missing data that reduce the validity of the questionnaire score.

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The lack of statistical significance observed due to the small sample size also suggests that a paradigm shift in study design for drug studies in dyspnea needs to occur, where patients most likely to benefit from opioid therapy for dyspnea, rather than every patient with dyspnea, are studied. Such paradigm shifts in study design are already starting to occur as seen by the use of adaptive designs in randomized controlled trials.21,22 Notably, the percentage of patients who received a blood transfusion 24 hours prior to study entry was higher in the responder compared to the nonresponder group (42.9% vs 22.2%, respectively), which may be a confounder for our study findings. However, previous studies evaluating the effect of transfusion on dyspnea had transfusion trigger thresholds and transfusion target hemoglobin concentrations for dyspnea relief of 8 and 10 g/dL, respectively, although there is so far no strong evidence for the benefit of transfusions to treat acute dyspnea.19,23 Our mean study hemoglobin concentration in responders and nonresponders was approximately 9 g/dL suggesting that whether anemia and prestudy transfusion had major contributions to dyspnea severity scores is highly debatable. Hence, evidence for the efficacy of fentanyl or other medications in treating acute dyspnea in the terminal stages of disease is realistically likely to remain confined to observational studies, despite the requirement of a large-scale, double-blind RCT for high-level evidence.2 Identifying nonburdensome objective measures for assessing dyspnea that can be used at various points in the dying trajectory as well as developing novel statistical analytical methods to analyze small sample sizes should thus be an important priority for dyspnea-related research at the end of life. To conclude, IV fentanyl appeared to palliate dyspnea in 7 of 16 patients with terminal cancer who had no anxiety or lung metastases at study entry, despite the lack of statistical significance. However, the difficulties in obtaining data and patients suggest that novel modifications to current study design and analysis may be required before undertaking further studies to objectively assess the efficacy of fentanyl in patients with acute dyspnea having terminal cancer.

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Acknowledgments

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We would like to acknowledge the National Cancer Centre Singapore Cancer Research Endowment Fund for funding to G.S. Pang and A.C.P. Yee for this study.

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Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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Funding The authors received no external financial support for the research, authorship, and/or publication of this article.

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Intravenous Fentanyl for Dyspnea at the End of Life: Lessons for Future Research in Dyspnea.

To determine the efficacy of intravenous (IV) Fentanyl in dyspnoeic patients with advanced cancer...
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