Table 1. Summary of Key Results for the Effects of Pharmacologic Interventions on Breathlessness in Patients With Advanced Cancer.
| Comparison | Evidence of difference | Strength of evidencea | No. of studies (No. analyzed) | Key findings | Conclusion |
|---|---|---|---|---|---|
| Placebo-controlled comparisons | |||||
| Opioids vs placebo | Equivalence | Moderate | 6 RCTs (N = 107); fentanyl vs placebo (4),16,17,18,19 hydromorphone (nebulized) vs hydromorphone (oral or subcutaneous) vs placebo (nebulized) (1),15 morphine vs placebo (1)20 | Pooled analysis with Charles et al15; saline vs nebulized hydromorphone comparison: SMD, −0.12; 95% CI, −0.45 to 0.20; I2 = 0.0%, P = .43; pooled analysis with Charles et al15: saline vs systemic hydromorphone comparison: SMD, −0.14; 95% CI: −0.47 to 0.18; I2 = 0.0%, P = .49 | Opioids were not more effective than placebo within the limits of the identified studies |
| Anxiolytics vs placebo | Equivalence | Low | 2 RCTs (N = 311); buspirone vs placebo (1),21 midazolam vs placebo (1)31 | Buspirone vs placebo: reported MBGD, −0.52; 95% CI, −1.045 to 0.005; midazolam vs placebo: no statistically significant difference between groups (P = .75) at 60 min; unable to calculate SMD, data presented as number of spray bottles rather than number of participants | Anxiolytics were no more effective than placebo |
| Corticosteroids vs placebo | No conclusion drawn | Insufficient | 1 RCT (N = 28); dexamethasone vs placebo (1)22 | Calculated SMD, −0.06; 95% CI, −0.70 to 0.58 | NA |
| Drug-drug comparisons | |||||
| Opioids vs opioids | Equivalence | Low | 7 RCTs (N = 132)15,23,24,27,28,30,32; subcutaneous vs sublingual morphine (1), subcutaneous vs nebulized morphine (1), high- vs low-dose sublingual fentanyl (1), low- vs high-dose opioids (drug unspecified) (1), hydromorphone (nebulized) vs hydromorphone (oral or subcutaneous) vs placebo (nebulized) (1), buccal fentanyl vs oral morphine (1), oral morphine hydrochloride vs oral morphine sulfate (1) | Pooled analysis: SMD, 0.15; 95% CI, −0.22 to 0.52; I2 = 4.8%, P = .37 | No difference in effectiveness between opioid doses or routes in improving breathlessness |
| Opioids vs anxiolytics | Equivalence | Low | 2 RCTs (N = 108)25,26; oral morphine vs oral midazolam (1), subcutaneous morphine vs subcutaneous midazolam vs combination (1) | For breathlessness intensity: 1 study found midazolam was more effective than morphine at 5 d (P < .001); another study found no significant differences between groups at 24 or 48 h; for categorical variable of percentage not experiencing breathlessness relief: calculated RR, 0.075; 95% CI, 0.004 to 1.270; calculated RR, 1.33; 95% CI, 1.02 to 1.75 | Opioids were not more effective than anxiolytics for improving breathlessness |
| Opioids vs corticosteroids vs bronchodilators | No conclusion drawn | Insufficient | 1 Retrospective cohort (N = 343)29; morphine vs methylprednisolone vs aminophylline (1) | Methylprednisolone vs aminophylline: calculated SMD, 0.41; 95% CI, 0.15 to 0.68; morphine vs aminophylline: calculated SMD, 1.18; 95% CI, 0.90 to 1.46; morphine vs methylprednisolone: calculated SMD, 0.76; 95% CI, 0.49 to 1.03 | NA |
Abbreviations: MBGD, mean between-group difference; NA, not applicable; RCT, randomized clinical trial; RR, relative risk; SMD, standardized mean difference.
a
Moderate strength indicates that further research may change the result; low strength indicates low confidence that the evidence reflects the true effect, and further research is very likely to change the result; and insufficient evidence indicates that evidence is unavailable or does not permit a conclusion.