This phase II trial studies fentanyl buccal tablet or morphine to see how well it works compared to a placebo in controlling shortness of breath during or after physical activity in cancer patients. Fentanyl sublingual tablet and morphine are opioids normally used to control pain that may also help to prevent or control shortness of breath during or after physical activity in cancer patients.

PRIMARY OBJECTIVE:

I. To compare the effect of prophylactic fentanyl buccal tablet (FBT), morphine sulfate, and placebo on the increase in the intensity of exertional dyspnea (0-10 point modified Borg scale) measured before versus at the end of a shuttle walk test (SWT).

SECONDARY OBJECTIVES:

I. To compare the effects of prophylactic FBT, morphine sulfate, and placebo on SWT distance and dyspnea unpleasantness, average daily dyspnea (intensity and unpleasantness, oxygen cost diagram), personalized daily activity (ability to complete activity), personalized dyspnea response, symptom burden (Edmonton Symptom Assessment System [ESAS]), quality of life (EuroQol-5 Dimension-5 Level [EQ-5D-5L]), and dyspnea severity and functional impairment based on the Patient Reported Outcomes Measurement Information System (PROMIS) dyspnea instruments.

II. To explore the effects of prophylactic FBT, morphine sulfate, and placebo on neurocognitive function, addictive potential (Drug Effects Questionnaire), adverse effects (Common Terminology Criteria for Adverse Events [CTCAE], Patient-Reported Outcomes version of CTCAE [PRO-CTCAE]), and pattern of opioid use.

OUTLINE: Patients are randomized to 1 of 3 groups.

GROUP I: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive FBT sublingually daily on days 6-19.

GROUP II: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive morphine orally (PO) daily on days 6-19.

GROUP III: Patients complete shuttle walk test on days 1, 5, 8, 12, 15, and 19. Patients also receive placebo (sublingually or PO) daily on days 6-19.

Inclusion Criteria:

1. Diagnosis of cancer with evidence of active disease
2. Dyspnea on exertion with an average intensity level ≥4/10 on a modified Borg scale
3. Outpatient at participating centers
4. Ambulatory and able to walk, with or without walking aid
5. On strong opioids with morphine equivalent daily dose (MEDD) of 60-400 mg for ≥1 wk (i.e. at least 4 out of 7 days), with stable (i.e. ±30%) regular dose over the last 3 d
6. Karnofsky performance status ≥40%
7. Age ≥18 yrs
8. Able to complete study assessments
9. Able to speak English or Spanish
10. Reside within 65 miles of participating centers or expected to visit MD Anderson in person at least once a month

Exclusion Criteria:

1. Dyspnea at rest ≥7/10 on modified Borg scale at enrollment
2. Supplemental oxygen requirement >6 L/min
3. Delirium (i.e. Memorial Delirium Assessment Scale ≥13)
4. History of unstable angina or myocardial infarction 1 mo prior to enrollment
5. Hemodynamic instability requiring hospitalization
6. History of substance use disorder or abnormal urinary drug screen within the past year, or at risk of opioid abuse as determined by Screener and Opioid Assessment for Patients with Pain (SOAPP14) ≥7
7. History of or known allergy to fentanyl or morphine sulfate
8. Using scheduled benzodiazepines at the time of enrollment and cannot stop during the study
9. Severe anemia (Hb <7 g/L) if documented in the last month and not corrected prior to study enrollment*
10. Bilirubin ≥5x upper limit of normal if documented in the last month and not lowered to <5x normal prior to enrollment*
11. Diagnosis of acute pulmonary embolism within past 2 wks
12. Diagnosis of pulmonary hypertension
13. Diagnosis of malignant pleural effusion with therapeutic thoracentesis expected in the next 2 wks
14. Currently pregnant or breastfeeding
15. Unwilling to provide informed consent