Effectiveness and safety of opioids for dyspnea in patients with lung cancer: secondary analysis of multicenter prospective observational study
Introduction
Dyspnea is one of the most prevalent and deteriorating symptoms in patients with cancer, especially those with lung cancer. Approximately 54–84% of patients with lung cancer present with some form of dyspnea, which are especially exacerbated in the terminal stages of the disease (1-7).
Patients with lung cancer can have interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), and other lung diseases (8-10). Pleural effusion, pleural dissemination and lung metastasis are common in patients with lung cancer (11). Radiation pneumonitis and drug-induced pneumonia may also affect dyspnea.
Opioids are considered the first choice of pharmacological treatment for cancer-induced dyspnea (12-17). Considering these, dyspnea in patients with lung cancer may be different from dyspnea in those with other cancer (i.e., may be mainly caused by lesions in the thoracic cavity. Moreover, patients with concomitant COPD are at risk for hypercapnia. However, few studies have evaluated the effectiveness and safety of opioids, in the real world, in patients with lung cancer. Therefore, this study examined the effectiveness and safety of opioids for dyspnea in patients with lung cancer and identified factors that influence their efficacy. We present the following article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-512/rc).
Methods
The present study is a secondary analysis of a multicenter prospective observational study that primarily aimed to evaluate the effectiveness and safety of opioids for dyspnea caused by cancer in Japan. Patients were enrolled between December 2019 and June 2021. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of National Hospital Organization Kinki-Chuo Chest Medical Center (approval number 2019-042). Informed consent was waived in this study because usual clinical practices, including treatments and assessments, were observed. We used an opt-out method so patients and families could refuse to participate in the study.
Patients
The participating sites were 12 institutions in Japan. The original research was a registry study on opioid therapy for dyspnea in cancer. The eligibility criteria for the original study are hospitalized adult patients with cancer starting regular opioid (morphine, oxycodone, hydromorphone, or fentanyl) administration (new, increased, switched, or combined with different opioids already administered) for dyspnea, and dyspnea on the Integrated Palliative Care Outcome Scale (IPOS) of ≥2 in the past 24 hours at baseline. Cases in which patients were already using opioids for other symptoms were included. Exclusion criteria are patients scheduled for therapeutic intervention for dyspnea due to conditions not directly related to cancer (e.g., antibiotics for bacterial pneumonia, or bronchodilator and corticosteroid for asthma attack or exacerbation of COPD) within 3 days of enrollment. In addition, patients scheduled to undergo an intervention within 3 days of enrollment that could cause a change in symptoms of dyspnea in a short period (e.g., chest drainage for pleural effusion, stenting for airway stenosis or superior vena cava stenosis). We included only patients with lung cancer who could document dyspnea Numerical Rating Scale (NRS) at baseline in the secondary analysis.
Procedure and measurements
We collected clinical data, including patients’ sociodemographic data [age, sex, primary tumor, site of metastasis, main cause of dyspnea as estimated by the treating physician, prognosis as estimated by the physician, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS), smoking history], comorbid lung disease (COPD, ILD) diagnosed based on clinical diagnosis, laboratory values (Cr, AST, ALT, T-Bil), type and morphine oral equivalent dose of previously administered opioids, concomitant interventions at study entry (benzodiazepines, corticosteroids). Furthermore, the dyspnea and anxiety scores of the IPOS for the previous 24 h and the dyspnea scores of current NRS, vital signs (respiratory rate, SpO2, oxygen dose), adverse events (nausea, drowsiness, delirium) assessed by Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, type of opioid administered, and morphine oral equivalent dose of opioid. At the baseline (T0), we collected clinical data, including patients’ sociodemographic data, anxiety (IPOS), comorbid lung disease and laboratory values within 1 month of study entry, type and dose of previously administered opioids, concomitant interventions at study entry, dyspnea score of IPOS and NRS, vital signs, adverse events, type of opioid administered and morphine oral equivalent dose of opioid at start of regular dosing. In the 24 (±12) (T1), 48 (±12) (T2) and 72 (±12) (T3) hours following the start of opioid treatment for dyspnea, we collected the dyspnea scores of the IPOS and NRS, vital signs, adverse events, type of opioid administered and morphine oral equivalent dose of opioid. IPOS is a 5-point objective symptom scale ranging from 0 (not at all) to 4 (overwhelmingly). NRS is a 11-point subjective symptom scale ranging from 0 (none) to 10 (worst).
Statistical analysis
Wilcoxon’s signed rank test with Bonferroni correction was used to compare NRS and IPOS/SATS scores over time. In sensitivity analysis, we imputed missing data with the last observational carried forward (LOCF) method. Univariate logistic regression analysis was performed with 1 or greater improvement in NRS score of dyspnea, which is Minimal Clinically Important Difference (MCID) of 1 point, (18) as dependent variable and age (≥75), sex, PS (≥3), smoking history, metastases, comorbidities, prognostic predictors, NRS score of dyspnea at baseline (≥7), IPOS anxiety score and opioid type as independent variables. Multivariate logistic regression analysis was performed with 1 or higher improvement in NRS score of dyspnea as dependent variable and age (≥75), sex, PS (≥3), smoking history, metastases, comorbidities, prognostic predictors, NRS score of dyspnea at baseline (≥7) and IPOS anxiety score as independent variables. Each independent variable was binarized if it was a continuous variable. Age and NRS score of dyspnea at baseline were binarized using the median. A P value <0.05 was considered statistically significant. All analyses were performed using JMP statistical software program (14th version, SAS Institute Inc., Cary, NC)
Results
Among the 402 patients who participated in the original study, 149 with lung cancer were extracted. Twenty-five patients without NRS score of dyspnea at baseline were excluded, and 124 were included in the analysis (Figure 1).
The median age at the time of opioid treatment was 74 years, and 84 patients (68%) were male, 107 (86%) had a PS score of 3–4, 78 (62.9%) had pleural effusion, and 60 (48.4%) had pleural dissemination. The major causes of dyspnea were lung tumor (n=57, 46.0%) and pleural effusion (n=30, 24.2%). Thirty-eight patients (30.6%) had COPD, and 21 (16.9%) had ILD. Fifty-nine patients (47.6%) were opioid-tolerant, and the median previous opioid’s morphine equivalent dose was 30 mg. The median NRS score of dyspnea was 6, and the median IPOS/STAS score of dyspnea was 3. Morphine was the most common opioid for dyspnea, with oxycodone second. The median opioid starting dose for opioid-naïve and opioid-tolerant patients were 12 mg and 32 mg, respectively (Table 1).
Table 1
| Characteristics | Value (N=124) |
|---|---|
| Median age [range], years | 74 [40–90] |
| Sex: male/female, n | 84/40 |
| Median body weight [range], kg | 50.9 [32–80] |
| Smoking history: Yes/No/Unknown, n | 91/32/1 |
| Performance status: 0–2/3–4, n | 17/107 |
| Metastatic site, n (%) | |
| Lung metastasis: Yes | 63 (50.8) |
| Pleural effusion: Yes | 78 (62.9) |
| Pleural dissemination: Yes | 60 (48.4) |
| Liver metastasis: Yes | 11 (8.9) |
| Main etiologies of dyspnea, n (%) | |
| Lung tumor: Yes | 57 (46.0) |
| Pleural effusion: Yes | 30 (24.2) |
| Cachexia/respiratory muscle fatigue: Yes | 1 (0.8) |
| Respiratory infection: Yes | 9 (7.3) |
| expectoration difficulty: Yes | 1 (0.8) |
| Anemia: Yes | 0 (0) |
| Carcinomatous lymphangitis: Yes | 14 (11.3) |
| Unidentifiable/others: Yes | 12 (9.7) |
| COPD: Yes | 38 (30.6) |
| Interstitial lung disease: Yes | 21 (16.9) |
| Concomitant medications, n (%) | |
| Benzodiazepine: Yes | 10 (8.1) |
| Corticosteroid: Yes | 55 (44.4) |
| Previous opioid, n (%) | |
| None | 65 (52.4) |
| Morphine | 11 (8.9) |
| Oxycodone | 16 (12.9) |
| Hydromorphone | 8 (6.5) |
| Fentanyl | 16 (12.9) |
| Tapentadol | 8 (6.5) |
| Tramadol | 1 (0.8) |
| Codeine phosphate | 1 (0.8) |
| Median previous opioid dose [range], mg | 30 [6–384] |
| Opioid for dyspnea: increase dose/switching/new start, n | 18/37/69 |
| Baseline status | |
| Median NRS score of dyspnea, n | 6 |
| Median IPOS/STAS score of dyspnea, n | 3 |
| Median respiratory rate [range], min | 20 [12–46] |
| Median SpO2 [range], % | 95 [79–100] |
| Median oxygen flow [range], L | 3 [0–50] |
| Opioid type: morphine/oxycodone/hydromorphone/fentanyl, n | 77/29/16/3 |
| Median opioid dose for opioid naive [range], mg | 12 [6–72] |
| Median opioid dose for opioid-tolerant [range], mg | 32 [6–384] |
COPD, chronic obstructive pulmonary disease; NRS, Numerical Rating Scale; IPOS, Integrated Palliative Care Outcome Scale; STAS, Support Team Assessment Schedule.
Both NRS and IPOS/STAS dyspnea scores significantly improved after 24 h of opioid initiation (mean difference: −1.64, 95% CI: −2.12 to −1.17; mean difference: −1.03, 95% CI: −1.21 to −0.85, respectively) (Table 2). Moreover, this improvement persisted even after correction by LOCF (Table S1).
Table 2
| Score | Mean difference (95% CI) | P value |
|---|---|---|
| NRS score of dyspnea | ||
| 24±12 hours (n=100) | −1.64 (−2.12 to −1.17) | <0.001* |
| 48±12 hours (n=85) | −1.86 (−2.32 to −1.40) | <0.001* |
| 72±12 hours (n=74) | −2.22 (−2.84 to −1.60) | <0.001* |
| IPOS/STAS score of dyspnea | ||
| 24±12 hours (n=113) | −1.03 (−1.21 to −0.85) | <0.001* |
| 48±12 hours (n=103) | −1.14 (−1.32 to −0.97) | <0.001* |
| 72±12 hours (n=90) | −1.19 (−1.39 to −0.99) | <0.001* |
*, P<0.05. CI, confidence interval; NRS, Numerical Rating Scale; IPOS, Integrated Palliative Care Outcome Scale; STAS, Support Team Assessment Schedule.
In the univariate logistic regression analysis of factors associated with NRS −1 or higher after 24 h, pleural dissemination was a response factor [odds ratio (OR): 2.71, 95% confidence interval (CI): 1.39–5.27, P=0.003], with poor effect in patients with physician prognosis of days (OR: 0.39, 95% CI: 0.20–0.77, P=0.007) (Table 3). In the multivariate logistic regression analysis of factors associated with NRS −1 or higher after 24 h, ILD was an independent and significant determinant (adjusted OR: 3.39, 95% CI: 1.34–11.09). Pleural dissemination tends to increase effectiveness (adjusted OR: 2.35, 95% CI: 0.95–5.79, P=0.064) and possibly less effective with physician prognosis of days (adjusted OR: 0.44, 95% CI: 0.18–1.07, P=0.071), however, they were not significant (Table 4).
Table 3
| Variables | Effective case (%) | OR | 95% CI | P value |
|---|---|---|---|---|
| Age ≥75 years (n=61) | 33 (54.1) | 1.01 | 0.50–2.04 | 0.988 |
| Male (n=84) | 45 (53.6) | 0.85 | 0.42–1.70 | 0.639 |
| Performance status: 3–4 (n=107) | 57 (53.3) | 0.53 | 0.19–1.48 | 0.228 |
| Respiratory rate ≥21 (n=59) | 30 (46.2) | 0.87 | 0.41–1.69 | 0.603 |
| History of smoking (n=91) | 48 (52.8) | 0.73 | 0.35–1.55 | 0.416 |
| Lung metastasis (n=63) | 35 (55.6) | 1.09 | 0.57–2.09 | 0.786 |
| Pleural dissemination (n=60) | 40 (66.7) | 2.71 | 1.39–5.27 | 0.003* |
| Pleural effusion (n=78) | 48 (61.5) | 1.88 | 0.95–3.74 | 0.072 |
| COPD (n=38) | 21 (55.3) | 1.42 | 0.69–2.91 | 0.345 |
| Interstitial lung disease (n=21) | 14 (66.7) | 1.70 | 0.72–4.05 | 0.227 |
| Physician prognosis of days (n=49) | 21 (42.9) | 0.39 | 0.20–0.77 | 0.007* |
| NRS score of dyspnea at baseline ≥7 (n=53) | 31 (58.5) | 1.37 | 0.67–2.81 | 0.390 |
| IPOS with anxiety (n=117) | 64 (54.7) | 1.99 | 0.49–8.02 | 0.333 |
*, P<0.05. OR, odds ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; NRS, Numerical Rating Scale; IPOS, Integrated Palliative Care Outcome Scale.
Table 4
| Variables | Adjusted OR | 95% CI | P value |
|---|---|---|---|
| Age ≥75 years (n=61) | 0.82 | 0.35–1.95 | 0.660 |
| Male (n=84) | 1.43 | 0.51–4.00 | 0.498 |
| Performance status: 3–4 (n=107) | 1.15 | 0.33–3.95 | 0.826 |
| Respiratory rate ≥21 (n=59) | 0.61 | 0.26–1.42 | 0.250 |
| History of smoking (n=91) | 0.92 | 0.28–3.00 | 0.889 |
| Lung metastasis (n=63) | 1.13 | 0.49–2.56 | 0.774 |
| Pleural dissemination (n=60) | 2.35 | 0.95–5.79 | 0.064** |
| Pleural effusion (n=78) | 1.97 | 0.80–4.87 | 0.142 |
| COPD (n=38) | 1.04 | 0.39–2.80 | 0.938 |
| Interstitial lung disease (n=21) | 3.39 | 1.34–11.09 | 0.043* |
| Physician prognosis of days (n=49) | 0.44 | 0.18–1.07 | 0.071** |
| NRS score of dyspnea at baseline ≥7 (n=53) | 1.80 | 0.79–4.11 | 0.161 |
| IPOS with anxiety (n=117) | 1.00 | 0.16–6.44 | 0.999 |
*, P<0.05; **, P<0.10. OR, odds ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; NRS, Numerical Rating Scale; IPOS, Integrated Palliative care Outcome Scale.
Regarding adverse events throughout the entire period, somnolence was the most common grade 3–4 adverse event (n=16, 12.9%), followed by delirium (n=9, 7.3%) (Table 5).
Table 5
| Adverse events | Grade 1–2 | Grade 3–4 |
|---|---|---|
| Nausea | 10 | 4 |
| Somnolence | 43 | 16 |
| Delirium | 24 | 9 |
There were 31 deaths during the observation period.
Discussion
To the best of our knowledge, this is the report with the largest sample size to clarify the effectiveness and safety of opioids for dyspnea in patients with lung cancer in real-world practice. Moreover, opioids may be more effective in patients with lung cancer with ILD and pleural dissemination and may be less effective in patients with a physician prognosis of days.
Most importantly, we demonstrated the effectiveness of opioids on dyspnea caused by lung cancer. Takahashi et al. have reported the effects of oral morphine on dyspnea in patients with cancer in a multicenter study, 90% of which were patients with lung cancer. Nevertheless, the sample size was small (n=80), and only morphine was used (13). Compared with their study, we observed the effectiveness of multiple opioids in 124 patients with lung cancer in this multicenter study. For dyspnea assessment, we used the NRS subjective scale and the IPOS/STAS clinician-rated scale. NRS score of dyspnea decreased by 1.64 points, greater than the MCID of 1 point (18). The effectiveness of opioids for dyspnea was also demonstrated in IPOS/STAS. In addition, the results were maintained in a sensitivity analysis. Therefore, opioids are considered effective for dyspnea in lung cancer.
Opioids were more effective in patients with lung cancer with ILD. ILD often presents with dyspnea, which is difficult to control. Efficacy of opioids for dyspnea in ILDs is controversial (19,20). A phase II study is planned to validate the results (21). Okabayashi et al. investigated whether concomitant ILD affects palliative pharmacotherapy for end-stage symptom relief in patients with lung cancer (22). They have reported that opioid dosage for patients with lung cancer did not change with or without ILD, but concomitant use of continuous midazolam and opioid was higher in patients with lung cancer with ILD, which means that dyspnea in patients with lung cancer and ILD may be more difficult to treat than dyspnea in those with lung cancer alone. This was inconsistent with our results. The number of patients with ILD in our study was only 21, therefore, further studies are warranted to reveal whether the coexistence of ILD affects the effectiveness of opioids for dyspnea in patients with lung cancer.
Opioids tended to be more effective for dyspnea in patients with lung cancer with pleural dissemination. In a survey among palliative care physicians to investigate physician-perceived predictive factors for the effectiveness of opioids in the treatment of cancer dyspnea, a high proportion of physician participants reported expecting opioids to be effective for treating dyspnea in patients with pleural lesions (23). This result is in line with our result. Opioids might modulate mismatch between the intended respiratory motor output set and the ventilatory output accomplished. In addition, a previous study reported that pain was associated with dyspnea in patients with lung cancer (24). Opioids may decrease pain from pleural lesions, making deep breathing possible, and might lead to improvement of dyspnea.
There was a trend for opioids to be less effective for dyspnea in patients with a physician prognosis of days. The aforementioned survey among palliative care physicians has also shown that 81% of physicians reported expecting opioids to be effective for the treatment of dyspnea in patients with ECOG PS 0–2 (23). As the disease progresses, the intensity of dyspnea increases, impairing the patient’s quality of life (2-7,25). It has been postulated that the principal cause of dyspnea is due to peripheral and respiratory muscle dysfunction, cardio-respiratory system disorder, and neuro-hormonal abnormalities (26). Various factors contribute to worsening dyspnea in patients with terminal lung cancer, including cachexia, multiple metastases to the chest, and worsening interstitial pneumonia. This combination of factors may make the treatment of dyspnea difficult in patients with lung cancer with a prognosis of days.
The percentage of grade 1–2 nausea, somnolence and delirium are 8%, 35% and 19%, respectively. Furthermore, the percentage of grade 3–4 nausea, somnolence and delirium are 3%, 13% and 7%, respectively. These were higher than in previous reports (12,13,15), but this may be because the previous studies were conducted at fixed doses or with small doses. Conversely, in this study, they were administered at the discretion of the attending physician.
This study has some limitations. First, this subgroup analysis was not preplanned. Therefore, the number of patients may not be sufficient for the analysis of patients with lung cancer. Second, due to the poor prognosis of the patient group, it was not possible to assess patient-reported dyspnea intensity over time for all patients. Third, the influence of non-opioid treatments such as benzodiazepines and oxygen administration cannot be ruled out because we did not assess these treatments to increase the feasibility. Fourth, placebo effect may influence the improvement of dyspnea. Fifth, we are only able to evaluate over 72 h. Sixth, we did not diagnose COPD and ILD with standard diagnostic criteria. Seventh, we evaluated only the presence of pleural effusion and not the volume of the effusion. Finally, due to the small number of cases, no comparison was made between patients already receiving opioids and those not receiving opioids.
In conclusion, opioids were effective for dyspnea in patients with lung cancer and safe. Further, opioids may be more effective in patients with lung cancer with ILD and pleural dissemination and may be less effective in patients with a physician prognosis of days.
Acknowledgments
We wish to thank JORTC for their assistance with this study. We wish to thank Editage (www.Editage.jp) for English language editing.
Funding: None.
Footnote
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-512/rc
Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-512/dss
Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-512/prf
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-22-512/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Review Board of National Hospital Organization Kinki-Chuo Chest Medical Center (approval number 2019-042). Informed consent was waived in this study because usual clinical practices, including treatments and assessments, were observed. We used an opt-out method so patients and families could refuse to participate in the study.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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